WO2004039816A1

WO2004039816A1 - Crystal of inorganic acid salt of cephem compound

Info

Publication number: WO2004039816A1
Application number: PCT/JP2003/013712
Authority: WO
Inventors: Fumihiko Matsubara; Yasuyuki Kawanishi; Satoru Ando
Original assignee: Shionogi & Co., Ltd.
Priority date: 2002-10-29
Filing date: 2003-10-27
Publication date: 2004-05-13
Also published as: TW200413396A; AU2003275682A1; JPWO2004039816A1

Abstract

Crystals of either an acid addition salt selected from the group consisting of the dihydrochloride, dihydrobromide, and dinitrate of the compound represented by the formula (I) or a solvate of the salt. The crystals are useful as a medicine for injection, etc.

Description

Specification

Crystal of inorganic acid salt of cephem compound

The present invention relates to crystals of various inorganic acid salts of cefm compounds useful as medical vegetables, and a method for producing the same. Background art

In general, cefm compounds useful as antibacterial agents are required to be of extremely high quality in the development of pharmaceuticals, especially injections, and have preferably been isolated as crystals. In particular, when used as an injection agent, crystals that are as excellent in water solubility and storage stability as possible have been demanded.

The cefm compound according to the present invention has the formula:

(Hereinafter, referred to as compound (I)). The corresponding monohydrochloride is known, but has been isolated only as amorphous (see Patent Document 1). As the crystals of compound (I), only the corresponding sulfate crystals have been isolated (see Non-Patent Document 1 and Patent Document 4). As examples of the inorganic acid salt crystals of the cephem compound other than the compound (I), there are known crystals of disulfate, dinitrate, dihydrochloride and phosphate (Patent Documents 2 and 3). See).

(Patent Document 1) WO 00/3266 (Example 6-2)

(Patent Literature 2) Japanese Patent Publication No. 62-10-300

(Patent Document 3) Japanese Patent Publication No. 2-99885

(Patent Document 4) WO 02/0 8 8 1 4 7 ' (Non-Patent Document 1) 41st ICAAC Program Collection (December 16-19, 2001, America, Chicago, Lecture No. F-370) Disclosure of Invention

In order to develop compound (I) as a drug, particularly as an injection, crystals that are more excellent in water solubility and Z or storage stability have been required.

As a result of intensive studies, the present inventors succeeded in converting the sulfate of compound (I) into crystals of other inorganic acid salts, and completed the present invention described below.

(1 set:

A crystal of an addition salt of an acid selected from the group consisting of dihydrochloric acid, dihydrobromic acid, and dinitric acid, or a solvate thereof, of the compound (I) represented by

(2) The crystal according to the above (1), which is a dihydrochloride or a hydrate thereof.

(3) The crystal according to the above (1), which is a 0.5 / 5-pentahydrate of a dihydrochloride.

(4) The crystal according to the above (1), which is a pentahydrate of dihydrochloride.

(5) In the powder X-ray diffraction pattern, the interplanar spacing (d) was mainly around 4.99, 4.89, 4.67, 4.57, 4.45, 4.'18, 3.70, 3.58, 3.43, 3.39 and 3.34 (unit: A). A crystal of the dihydrochloride or a hydrate thereof according to the above (1), which shows a peak.

(6) The crystal according to the above (5), which is a pentahydrate of dihydrochloride.

(7) The crystal according to the above (1), which is a 0.5 hydrate of dihydrochloride.

(8) In the powder X-ray diffraction pattern, the spacing (d) was 9.52, 5.10, 4.49, 3.87, 3.66, 3.56, 3.47, 3.40, 3.37, 3.30, 3.24, 3.18, 3.11, and 2.79 (unit: A) A crystal of the dihydrochloride or a hydrate thereof according to the above (1), showing a main peak in the vicinity. (9) The crystal according to the above (8), which is a 0.5 hydrate of dihydrochloride.

(10) The crystal according to the above (1), which is dihydrobromide or a hydrate thereof.

(11) The crystal according to the above (1), which is 0.5 to pentahydrate of dihydrobromide.

(12) The crystal according to the above (1), which is tetrahydrate of dihydrobromide.

(13) In the powder X-ray diffraction pattern, the interplanar spacing (d) shows main peaks around 5.29, 4.45, 4.28, 3.65, 3.52, 3.42, 3.35 and 3.12 (unit: A). (1) A crystal of the described dihydrobromide or a hydrate thereof.

(14) The crystal according to the above (13), which is a tetrahydrate of dihydrobromide.

(15) The crystal according to the above (1), which is a hemihydrate of dihydrobromide.

(16) The crystal according to the above (1), which is dinitrate or a hydrate thereof.

(17) The crystal according to the above (1), which is 0.5 to pentahydrate of dinitrate.

(18) The crystal according to the above (1), which is a trihydrate of dinitrate.

(19) In the powder X-ray diffraction pattern, the plane spacing (d) is mainly around 5.34, 5.13, 5.01, 4.83, 4.64, 4.57, 4.43, 4.16, 4.06, 3.71, 3.40, 3.39, 3.33 (unit: A). Crystals of the dinitrate or hydrate thereof according to the above (1), which shows a strong peak.

(20) The crystal according to the above (19), which is a trihydrate of dinitrate.

(2 1) The crystal according to the above (1), which is a hemihydrate of dinitrate.

(22) In the powder X-ray diffraction pattern, the plane spacing (d) was 9.60,9.24,6.89,5.15,5.05,4.52,4.05,3.98,3.94,3.68,3.51,3.33,3.25,2.89, and 2.88 (unit: (A) A crystal of the dinitrate or a hydrate thereof according to (1) above, which shows a main peak near.

(23) The crystal according to the above (22), which is a hemihydrate of dinitrate.

(24) A pharmaceutical composition comprising the crystal according to any one of the above (1) to (23).

(25) The pharmaceutical composition according to the above (24), which is an antibacterial agent and an injection.

(26) A method for preventing or treating bacterial infectious diseases, comprising administering the crystal according to any one of (1) to (23).

(27) Use of the crystal according to any one of (1) to (23) for producing a prophylactic or therapeutic agent for bacterial infection. (28) An acid addition salt of the compound (I) according to the above (1) or a solvent thereof, wherein the monosulfate of the compound (I) and an acid are mixed, and the mixture is precipitated by adding an alcohol. Method for producing Japanese crystal.

(29) Barium chloride, barium nitrate, barium bromide, or barium hydroxide is added to a monosulfate aqueous solution of compound (I) in the presence of an acid, if necessary, to precipitate and remove barium sulfate. A method for producing a crystal of an acid addition salt of the compound (I) or a solvate thereof according to the above (1), wherein an alcohol is added to the residue. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph of powder X-ray diffraction of dihydrochloride crystals obtained in Example 1. The vertical axis represents the peak intensity (unit: cps), and the horizontal axis represents the diffraction angle 2Θ (unit: °).

FIG. 2 is a graph of powder X-ray diffraction of the dihydrobromide crystals obtained in Example 2.

FIG. 3 is a graph of powder X-ray diffraction of dinitrate crystals obtained in Example 3.

FIG. 4 is a graph of powder X-ray diffraction of the dihydrochloride crystals obtained in Example 4 (2).

FIG. 5 is a graph of powder X-ray diffraction of dinitrate crystals obtained in Example 6 (2). BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the acid addition salt of compound (I) of the present invention include dihydrochloride, dihydrobromide, and dinitrate. The present invention provides crystals of these inorganic acid salts or solvates thereof, more preferably hydrate crystals.

Examples of the solvent of the solvate include water, alcohol (eg, methanol, ethanol, isopropanol, etc.), tetrahydrofuran, acetone, dioxane, and a mixture thereof. The solvation number varies depending on the production method, storage conditions and the like, and is not necessarily limited. However, when used as a pharmaceutical, the content of the organic solvent is preferably small. The solvate is preferably a hydrate. The hydration number is preferably 0.5-6, more preferably 0.5-5.

Hereinafter, each salt will be described. C 1) dihydrochloride

The dihydrochloride crystals are preferably hydrates. The water content is preferably 0.5 to 6 equivalents, more preferably 0.5 to 5 equivalents, still more preferably 0.5 to 4 equivalents, or 0.5 to 3 equivalents to compound (I).

Examples of the crystals include those whose powder X-ray diffraction pattern includes a representative peak in the vicinity shown below. The crystal of the present invention is preferably a single crystal, but may be a mixture thereof.

1—Type A:

Spacing (d) = 4.99, 4.89, 4.67, 4.57, 4.45, 4.18, 3.70, 3.58, 3.43, 3.39 and 3.34 (unit: A)

The type A crystal is preferably pentahydrate.

1—Type B:

Spacing (d) = 9.52, 5.10, 4.49, 3.87, 3.66, 3.56, 3.47, 3.40, 3.37, 3.30, 3.24, 3.18, 3.11, and 2.79 (unit: A)

The type B crystals are preferably hemihydrate.

Compound (I) was conventionally isolated in a non-crystalline state as the monohydrochloride, but this time it could be crystallized by converting it to the dihydrochloride.

(2) dihydrobromide crystals

The dihydrobromide crystals are preferably hydrates. The water content is preferably 0.5 to 6 equivalents, more preferably 0.5 to 5 equivalents, still more preferably 0.5 to 4 equivalents or 0.5 to 3 equivalents to compound (I).

2—Type A:

The surface spacing (d) is 5.29, 4.45, 4.28, 3.65, 3.52, 3.42, 3.35 and 3.12 (unit: A). Form 2-A is preferably tetrahydrate.

As another crystal, a pentahydrate crystal is also preferable.

(3) Dinitrate crystals

The dinitrate crystals are preferably hydrates. The water content is preferably 0.5 to 6 equivalents, more preferably 0.5 to 5 equivalents, and still more preferably 0.5 to 4 equivalents, relative to compound (I).

Type 31 A:

Plane spacing (d) = 5.34, 5.13, 5.01, 4.83, 4.64, 4.57, 4.43, 4.16, 4.06, 3.71, 3.40, 3.39, 3.33 (unit: A)

The 3-A crystal is preferably tri-hydrate.

3-B type:

Spacing (d) = 9.60, 9.24, 6.89, 5.15, 5.05, 4.52, 4.05, 3.98, 3.94, 3.68, 3.51, 3.33, 3.25, 2.89, and 2.88 (unit: A)

Form 3-B is preferably 0.5 hydrate. The above-mentioned plane spacing (d) value is obtained by selecting a representative peak among the X-ray peaks of each crystal, and each crystal structure is not necessarily limited only by these values. That is, peaks other than these may be included. In general, when a crystal is measured by X-ray diffraction, its peak may cause some measurement error depending on the measuring instrument, measuring conditions, presence of an adherent solvent, and the like. Thus, all crystals characterized by an X-ray pattern substantially similar to the above are within the scope of the invention. The method for producing the crystals of the inorganic acid salt of the compound (I) or a solvate thereof is not particularly limited, but it may be preferably produced according to the following method. (Method 1)

After mixing a sulfate (eg, monosulfate) of compound (I) with an acid, and adding an organic solvent such as an alcohol (eg, methanol, ethanol, isopropanol, etc.), the crystals of the inorganic salt other than the sulfate are added. Precipitates.

The amount of the acid is usually about 2 molar equivalents or more, preferably about 5 molar equivalents or more, more preferably about 10 molar equivalents or more based on one sulfate.

The crystallization is preferably performed by adding a seed crystal, and is carried out by allowing to stand at about 0 ° C to room temperature, preferably about 10 ° C.

The concentration of the acid is preferably about 1 to 10%. Particularly in the case of hydrochloric acid, about 1 to 5% is preferred. In the case of hydrobromic acid, about 1 to 5% is preferable. In the case of nitric acid, about 1-5% is preferred.

1 The mixing method and order of the sulfate and the acid are not particularly limited, but may be appropriately determined according to the type of the acid and the like.

(Method 2)

A barium salt such as barium chloride, barium nitrate, barium chloride, or barium hydroxide is added to an aqueous solution of a sulfate (e.g., monosulfate) of compound (I) in the presence of the above-mentioned acid, if necessary, in the presence of the above-mentioned acid. Precipitate barium and remove it by filtration or the like. Next, by adding alcohol and, if desired, water to the residue such as the filtrate and the washing solution, crystals of inorganic acid salts other than sulfate precipitate.

Here, the addition of the acid “in the presence of an acid” may be performed simultaneously with, before or after the addition of the barium salt. The precipitated barium sulfate may be filtered and washed with an acid. Alternatively, an aqueous solution of a palladium salt may be prepared in advance, and then the monosulfate of compound (I) may be added.

The potassium salt is preferably about :! to the monosulfate of compound (I). 22 molar equivalents, more preferably about 1-1,5 molar equivalents are used.

When an acid is used, the acid is preferably used in an amount of at least about 2 molar equivalents, more preferably at least about 5 molar equivalents, relative to the monosulfate of compound (I).

More preferably, by repeating each of the crystallization methods (1) and (2), Highly pure crystals can be obtained. The sulfate of compound (I) used as a raw material may be ^ -crystal or amorphous, and may be a hydrate or an anhydrate.

By drying the crystals obtained by the above-mentioned method at room temperature or under reduced pressure by a conventional method, the number of solvents can be adjusted, and a desired hydrate or the like can be obtained.

The crystals of the inorganic acid salt of the compound (I) of the present invention are excellent in water solubility, storage stability, ease of drying, handleability in formulation, and the like, and are themselves useful as pharmaceutically active ingredients. . It can also be used as an intermediate for producing a sulfate of compound (I).

The present invention further provides a pharmaceutical composition comprising, as an active ingredient, a crystal of an inorganic acid salt of the compound (e) or a solvate thereof. The pharmaceutical composition is preferably an antimicrobial agent. Examples of the dosage form of the pharmaceutical composition include tablets, granules, capsules, injections, etc., and preferably injections. The high water solubility of the crystals of the present invention is very advantageous in preparing an injection at the point of use in medical practice, without the risk of turbidity. The weakly acidic to near neutral in terms of injection (eg: pH 4 - 7) in the case of pH adjustment, pH adjustment Seizai bases such as optionally _{_{(eg: NaOH, NaHC0 3, Na 2}} C0 3, amino acids, etc.) Although usable in combination, Na C 1 produced by neutralization of the hydrochloride salt of the present invention for example, the effect on the living body is relaxed as compared to Na ₂ S 0 ₄ caused when neutralized corresponding sulfate . Therefore, the hydrochloride crystals of the present invention are particularly suitable as injections.

The injection can be prepared as a powder-filled preparation or a lyophilized preparation.

The above-mentioned pharmaceutical composition may optionally contain a pharmaceutical additive (eg, excipient, disintegrant, dissolving agent, emulsifier, stabilizing agent, etc.). Particularly when used as an injection, along with distilled ice or physiological saline, pH regulators agent (e.g. _{_{:: NaOH, NaHC0 3, Na 2}} C0 3, amino acids) may be incorporated.

The dosage of the crystals of the inorganic acid salt of the compound (I) or a solvate thereof varies depending on the patient's age, the type and condition of the disease, and the like. Preferably, about 0.5 to 5 Omg / day may be administered in 1 to 2 to 4 divided doses, if desired.

Furthermore, the present invention provides a method for administering a crystal of the present invention to an animal including a human, Provided is a method for preventing or treating infectious diseases.

The present invention also provides a method for using the crystal of the present invention for producing a prophylactic or therapeutic agent for bacterial infection. In this case, the crystal of the present invention itself may be a pharmaceutically active ingredient, or may be used as an intermediate of a pharmaceutical preparation containing another salt such as a sulfate.

Examples and test examples are shown below. The X-ray measurement conditions are: Cu K ray (wavelength = 1.54 A), tube voltage 40 kV, tube current 30 mA, scan speed: 4.000 ° / min, sampling width: 0.020 °.

Example 1 (dihydrochloride pentahydrate)

(1) Preparation of seed crystal

After dissolving monosulfate .2 hydrate (2 g, 2.72 mmol) of compound (I) obtained according to the method described in WO 02/088147 in 30 ml (11 molar equivalents) of IN hydrochloric acid, ethanol 70 was added. l was added and left at 10 ° C. After one night, the precipitated crystals were collected with a spatula, air-dried, and used as seed crystals of dihydrochloride.

(2) Salt exchange method

Compound (I) monosulfate trihydrate (10 g, 13.3 mmole) was dissolved in 85 ml (12.8 mole equivalent) of 2N hydrochloric acid, and 510 ml of ethanol was added under ice-cooling. Hydrochloride seed crystals were added, and the mixture was stirred at 10 ° C overnight. The precipitated crystals were collected by filtration, washed twice with 25 ml of 90 ° ethanol and twice with 25 ml of ethanol, and then air-dried at room temperature to obtain 6.35 g of crystals. The composition of these crystals was dihydrochloride / 2-sulfate = 75/25 (pentahydrate) based on elemental analysis. When 6 g of the obtained crystals were recrystallized by the same method, 4. g of crystals of dihydrochloride / 1 sulfate = 95/5 (pentahydrate) were obtained. Further, 3.1 g of the crystal was recrystallized by the same method to obtain 4.14 g of dihydrochloride / 1 sulfate = 100/0 (5 hydrate).

(3) B a C 1 ₂ method

Dissolve the monosulfate (9.1 g water) (60 g, 78 nLHole) of compound (I) in 130 ml (10 mole equivalent) of 6N hydrochloric acid, and add 19.07 g (1 mole equivalent) of barium chloride dihydrate under ice-cooling. A 55 ml solution of water was added dropwise. After stirring at room temperature for 30 minutes, the precipitated barium sulfate was removed by filtration and washed with 60 ml of water. Collect the filtrate and washings, add 875 ml of ethanol and 15 ml of ice under ice-cooling. After that, seed crystals of the dihydrochloride obtained in (1) were added, and the mixture was stirred at 10 ° C for a while. The precipitated crystals were collected by filtration, washed successively twice with 100 ml of 85 ethanol and twice with 100 ml of ethanol, and air-dried at room temperature to obtain 40.29 g of crystals. The crystals were found to be dihydrochloride pentahydrate by elemental analysis.

Anal. Calcd. For _{24 8} „02HG1 * 5¾0

: C, 37.74; H, 5.28 ; N, 18.34; S, 8.40; C1,9.30; H 2 0,11.79%

Found: C, 37.77; H, 5.20; N, 18.38; S, 8.42; Cl, 8.96; H 2 0, 11.66%

The powder X-ray diffraction pattern of the dihydrochloride pentahydrate crystal is shown in FIG.

(table 1)

Example 2 (dihydrobromide tetrahydrate)

(1) Ba (OH) ₂ method

To a solution of 2 g (2.66 mmol) of monosulfate (3 hydrate) of compound (I) in 3 ml of water was added 1.54 ml (5 mole equivalents) of 47% hydrogen bromide It and then barium hydroxide (8 (Hydrate) 0.838 g (1 mole equivalent) of 4 ml of water was injected. The precipitated parium sulfate was filtered and washed with 2 ml of water to remove. The filtrate and the washings were collected, and after adding 24 ml of isopropanol under ice-cooling, the mixture was stirred at 10 ° C overnight. The precipitated crystals were collected by filtration, washed successively with 10 ml of 80% isopropanol and 10 ml of isopropanol, and air-dried at room temperature to obtain 1.50 g of crystals.

Of these, 0.50 g (0.59 m mole) was dissolved in a mixture of 1.6 ml of water and 0.4 ml (5 mole equivalent) of 47% hydrobromic acid, and a trace amount of insoluble matter was filtered and washed with 1 ml of water. The filtrate and the washings were collected, 6 ml of isopropanol was added under ice-cooling, and the crystals obtained above were added as seed crystals, followed by stirring overnight at 1 CTC. The precipitated crystals were collected by filtration, washed successively with 6 ml of 80% isopropanol and 6 ml of isopropanol, and air-dried at room temperature to obtain 0.28 g of crystals. The crystals were found to be dihydrobromide tetrahydrate by elemental analysis.

Anal. Calcd. For (^ Ι ^ Ι ^ Ο ^; 2HBr4¾0

: C, 34.54; H, 4.59 ; N, 16.78; S, 7.68; Br, 19.15; H 2 0,8.63%

_{Found: C, 34.56 H 5 4.55} N, 16.75 S, 7.52 Br, 19.20 Hj0,8.97%

(Table 2)

Example 3 (Dinitrate · trihydrate)

(1) Preparation of seed crystal

Compound (I) monosulfate 'trihydrate (2 g, 2.66 mmol) was dissolved in 8 ml of water, and a solution of 695 mg (1 molar equivalent) of parium nitrate in 8 ml of water was added dropwise at room temperature. At 30 minutes While stirring. The precipitated barium sulfate precipitate was separated by filtration and washed with water 2ια1. The filtrate and washings were collected, and 50 ml of ethanol was added under ice cooling. Since the preparation was slightly turbid, 2 ml of water was further added to make a clear solution. The prepared solution was stirred at 10 ° C overnight, but no precipitation of crystals was observed. Further, 2.02 l (10 molar equivalents) of 60% nitric acid and 40 ml of ethanol were added under ice cooling. Stirring and standing were repeated at C for 7 days. The precipitated crystals were collected by filtration and washed twice with 5 ml of 80% ethanol water to obtain 0.30 g of crystals. This crystal was found to be equivalent to dinitrate 3.1 hydrate by elemental analysis.

Anal. Calcd. For C _{! (} H _{! A} N ₁₀ OsS ₂ · 2H 0 ₃ · 3.1¾0

: 0,36.84; ¾4.66; ^ 21.48; 8,8.19; ¾0,7.14%

Found: C, 36.69; H, 4.66 ii, 21.50 S, 8.22 H _{! 0,} 7.34

(2) Ba (N0 ₃ ) ₂ method

A solution of 20.83 g (1 mole equivalent) of barium nitrate in 240 ml of water was charged with a monosulfate / 3-hydrate (60 g, 78 mmol) of compound (I) for 5 minutes at room temperature. After stirring at room temperature for 30 minutes, the precipitated sulfate was filtered off and washed with a mixture of 29.7 ml of water and 30.3 ml (5 mole equivalents) of 60% nitric acid to remove it. The filtrate and the washings were collected, and 510 ml of ethanol was added under ice-cooling. Then, seed crystals of the nitrate obtained in (1) were added, and the mixture was stirred overnight at 1 CTC. The precipitated crystals were collected by filtration, washed twice with 60 ml of 80% ethanol and twice with 60 ml of ethanol, and then air-dried at room temperature to obtain 8.95 g of crystals. The crystals were dinitrate / 3-hydrate according to elemental analysis. Anal. Calcd. For

· 2 丽 0 ₃ · 3¾0

: C, 36.92; H, 4.65; W, 21.53; S, 8.21; 0,6.92%

Found: C, 36.89 H, 4.49 N ₃ 21.54; S, 8.28; H _{! 0,} 7.06

The X-ray powder diffraction pattern of this crystal is shown in FIG. W

(Table 3)

Example 4 (dihydrochloride · 0.5 hydrate)

(1) Dissolve crystals (4 (^ (52.4 111 mole)) of dihydrochloride * pentahydrate obtained in Example 1 (3) in 100 ml of 2N hydrochloric acid, filter, and filter, then add 31 ml of 2N hydrochloric acid (total). The filtrate and washings were collected, 435 ml of ethanol was added under ice-cooling, seed crystals were added, and the mixture was stirred overnight at 10 ° C. The precipitated crystals were collected by filtration. After washing twice with 50 ml of 85% ethanol and twice with 50 ml of ethanol, and then air-dried at room temperature, 30.59 g of crystals were obtained. It was a hydrate.

Anal.Calcd.for C ₂₄ H ₂₈ N ₁₀ O ₅ S ₂ 2HC1 '5H ₂ 0

: C, 37.74; H, 5.28; N, 18.34; S, 8.40; C1, 9.30; ¾0, 11.79%

Found: C, 37.86; H, 5.12; N, 18.51; S, 8.33; C1, 9.05; ¾0, 11.74%

8.00 g of the above dihydrochloride · pentahydrate was dried under reduced pressure at room temperature for 5 hours to obtain 7.17 g of the compound (I) dihydrochloride · hemihydrate crystal. Anal.Calcd.for C ₂₄ H ₂₈ N ₁₀ O ₅ S ₂ 2HC10.5H ₂ O

: C, 42.23; H, 4.58 ; N, 20.52; S, 9.39; CI, 10.39; H 2 0, 1.32%

Found: C, 42.03; H, 4.53; N, 20.56; S, 9.39; CI, 10.13; H 2 0, 1.69%

(2) Dissolve 60 g (78.0 mmole) of the monosulfate tetrahydrate of compound (I) in 130 ml (10 molar equivalents) of 6N hydrochloric acid, and cool with ice under barium chloride dihydrate. A solution of 19.07 g (l molar equivalent) of the product in 55 ml of water was added little by little, and the mixture was stirred at room temperature for 30 minutes. The precipitated barium sulfate was removed by filtration and washed with 60 ml of water. The filtrate and the washings were collected, and under ice-cooling, 875 ml of ethanol and 15 ml of water were added. The seed crystals obtained above were added, and the mixture was stirred overnight at 1 CTC. The precipitated crystals were collected by filtration, washed twice with 100 ml of 85% ethanol and twice with 100 ml of ethanol, and air-dried at room temperature to obtain 40.29 g of crystals. The crystals were found to be dihydrochloride pentahydrate by elemental analysis.

_{_{_{Anal.Calcd.for C 24 H 28 N 10 O}}} 5 S 2. 2HC1. 5H 2 0

: C, 37.74; H, 5.28 ; N, 18.34; S, 8.40; CI, 9.30; H 2 0, 11.79%

Found: C, 37.77; H, 5.20; N, 18.38; S, 8.42; CI, 8.96; ¾0, 11.66%

1.00 g of the above-mentioned dihydrochloride pentahydrate was dried under reduced pressure at room temperature for 10 hours to obtain 0.90 g of dihydrochloride-hemihydrate of compound (I). The powder X-ray diffraction pattern (measured in a relative humidity of 5%) is shown in FIG.

_{_{_{Anal.Calcd.for C 24 H 28 N 10 O}}} 5 S 2 - 2HC1 · 0.5H 2 O

: C, 42.23; H, 4.58; N, 20.52; S, 9.39; C1, 10.39; ¾0, 1.32%

Found: C, 42.03; H, 4.57; N, 20.49; S, 9.23; C1, 10.01; ¾0, 0.97%

(Table 4)

Example 5 (dihydrobromide salt / hemihydrate)

(1) To a solution of 8.86 g (1 molar equivalent) of palladium dibromide dihydrate in 50 ml of water, add 20 g (26.6 mmol) of compound (I) monosulfate and trihydrate in small portions. The mixture was stirred at room temperature for 30 minutes. The precipitated parium sulfate was filtered and washed and removed with a solution of 15.4 ml (5 molar equivalents) of 47% hydrobromic acid in 55 ml of water. The filtrate and the washings were collected, and after adding 210 ml of isopropanol under ice-cooling, the mixture was stirred overnight at 1 CTC. The precipitated crystals were collected by filtration, washed with 60% 80% isopropanol and 60 ml of isopropanol, and air-dried at room temperature to obtain 12.50 g of crystals. 12.50 g (14.98 mmol) of these crystals was dissolved in a mixture of 29 ml of water and 8.71 ml (5 molar equivalents) of 47% hydrobromic acid, and a trace amount of insolubles were filtered and washed with 25 ml of water. The filtrate and washings were collected, and 125 ml of isopropanol was added under ice-cooling. The crystals obtained above were added as seed crystals, and the mixture was stirred overnight at 10 ° C. The precipitated crystals were collected by filtration, washed successively with 60 ml of 80% isopropanol and 60 ml of isopropanol, and air-dried at room temperature to obtain 9.14 g of crystals. The crystals were found to be dihydrobromide tetrahydrate by elemental analysis.

_{_{_{Anal.Calcd.for C 24 H 28 N 10 O}}} 5 S 2 · 2HBr · 4H 2 0

C, 34.54; H, 4.59; N, 16.78; S, 7.68; Br, 19.15; H 2 0, 8.63%

Found: C, 34.80; H, 4.48; N, 16.84; S, 7.57; Br, 18.70; H 2 0, 8.20% 8.14 g of the above-mentioned dihydrobromide tetrahydrate was dried under reduced pressure at room temperature for 4 hours to obtain 7.51 g of a dihydrobromide salt of compound (I) -pentahydrate.

Anal.Calcd.for C ₂₄ H ₂₈ N ₁₀ O ₅ S ₂ 2HBr0.5H ₂ O

: C, 37.36; H, 4.05; N, 18.16; S, 8.31; Br, 20.71; ¾0, 1.17%

Found: C, 37.63; H, 4.21; N, 18.19; S, 8.30; Br, 20.26; H 2 0, 1.27% Example 6 (2 nitrate, 0.5 Ice hydrate)

(1) Dissolve 28.5 g (36.5 mmol) of crystals of dinitrate * 3 hydrate obtained in Example 3 (2) in 80 ml of 8.4% nitric acid, filter and filter, then 18.4 ml of 8.4% nitric acid (total 99.4 ml) , 5 molar equivalents). The filtrate and the washings were collected, and 168 ml of ethanol was added under ice-cooling. The crystals obtained above were added as seed crystals, and the mixture was stirred at 10 ° C overnight. The precipitated crystals were collected by filtration, washed twice with 30 ml of 80% ethanol and twice with 30 ml of ethanol, and then air-dried at room temperature to obtain 23.03 g of crystals. The crystals were found to be dinitrate / 3 hydrate by elemental analysis.

Anal.Calcd.for C ₂₄ H ₂₈ N ₁₀ 0 ₅ S ₂ 2HN 0 ₃ 3H ₂ 0

C, 36.92; H, 4.65; N, 21.53; S, 8.21; H 2 0, 6.92%

Found: C, 36.73; H, 4.54; N, 21.62; S, 8.23; H 2 0, 6.96%

8.00 g of the above dinitrate · trihydrate was dried under reduced pressure at room temperature for 5 hours to obtain 7.51 g of a dinitrate · hemihydrate crystal of compound (I).

Anal.Calcd.for C ₂₄ H ₂₈ N ₁₀ O ₅ S ₂ 2HN0 ₃ * 0.5H ₂ O

: C, 39.18; H, 4.25 ; N, 22.85; S, 8.72; H 2 0, 1.22%

Found: C, 39.06; H, 4.19; N, 22.94; S, 8.69; H 2 0, 1.17%

(2) To a solution of 20.83 g (l molar equivalent) of barium dinitrate in 240 ml of water, crystal SO g (79.7 mmol) of monosulfate / trihydrate was added little by little, and the mixture was stirred at room temperature for 30 minutes. The precipitated barium sulfate was removed by filtration and washed with a mixed solution of 30.3 ml (5 molar equivalents) of 60% nitric acid and 29.7 ml of water. The filtrate and washings were collected, and 510 ml of ethanol was added under ice-cooling. The seed crystal obtained above was added, and the mixture was stirred at 10 ° C overnight. The precipitated crystals are collected by filtration, twice with 60 ml of 80% ethanol, and with 60 ml of ethanol.

After washing twice and air-drying at room temperature, 28.95 g of crystals were obtained. 28.5 g of this crystal (36.5 m was dissolved in 80 ml of 8.4% nitric acid, filtered, and washed with 19.4 ml of 8.4% nitric acid (99.4 ml, 5 molar equivalents). The filtrate and washings were collected, and 168 ml of ethanol was added under ice-cooling. The crystals obtained above were added as seed crystals, and the mixture was stirred at 10 ° C overnight. The precipitated crystals were collected by filtration, washed successively twice with 30 ml of 80% ethanol and twice with 30 ml of ethanol, and air-dried at room temperature to obtain 23.03 g of crystals. The crystals were dinitrate / 3-hydrate according to elemental analysis.

_{_{_{Anal.Calcd.for C 24 H 28 N 10 O}}} 5 S 2. 2ΗΝ0 3 · 3H 2 0

: C, 36.92; H, 4.65 ; N, 21.53; S, 8.21; H 2 0, 6.92%

Found: C, 36.73; H, 4.54; N, 21.62; S, 8.23; ¾0, 6.96%

1.00 g of the above dinitrate * trihydrate was dried under reduced pressure at room temperature for 10 hours to obtain 0.94 g of dinitrate · α.pentahydrate of the compound (I). The powder X-ray diffraction pattern (measured in a relative humidity of 5%) is shown in FIG.

_{_{_{Anal.Calcd.for C 24 H 28 N 10 O}}} 5 S 2 · 2ΗΝ0 3 · 0.5H 2 O

: C, 39.18; H, 4.25 ; N, 22.85; S, 8.72; H 2 0, 1.22%

Found: C, 39.34; H, 4.37; N, 22.89; S, 8.44; H 2 0, 1.08%

(Table 5)

Peak

2 θ Half width d value Intensity Relative intensity No.

1 9.200 0.188 9.6046 374 5

2 9.560 0.212 9.2437 436 5

3 12.840 0.212 6.8888 255 3

4 17.220 0.188 5.1452 354 5

5 17.560 0.235 5.0464 362 5

6 19.620 0.541 4.5209 592 7

7 21.920 0.400 4.0515 366 5

8 22.320 0.188 3.9798 300 4

9 22.540 0.282 3.9414 322 4

10 24.180 0.588 3.6777 596 7

11 25.320 0.565 3.5146 595 7

12 26.760 0.212 3.3287 798 10

13 27.440 0-306 3.2477 1300 15

14 30.920 0.188 2.8896 322 4

15 31.020 0.212 2.8806 232 4 Test Example 1 (Solubility)

The solubility of each inorganic acid salt crystal of the compound (I) obtained in the above example was examined. After adding an excessive amount of crystals to the solvent and stirring the mixture at room temperature (25 ° C) for 3 hours, the solution was examined by a method for quantifying HPLC. The corresponding monosulfate crystals (dihydrate) were used as controls.

(Table 6)

Each of the dihydrochloride and dinitrate crystals of compound (I) showed higher solubility in water or saline than the corresponding monosulfate crystals. Test Example 2 (Storage stability)

Each crystal of the compound (I) of the present invention was subjected to a stability test at 50 ° C. The corresponding monosulfate crystals (0-5 and monohydrate) were used as controls.

(Test method)

1-Accurately weigh BVK-14 Pierre and CB-9 rubber stopper to encapsulate bulk powder.

2. Weigh approximately 100 mg (potency) of the bulk powder in a dry pork humidified to less than 5¾ RH into a vial and stopper.

3. Weigh the vial containing the bulk powder precisely and calculate the bulk volume.

4. Use the freeze-dried product for the calibration curve and measure the initial content.

The quantification is performed by HPLC.

Column: YMC-Pack 0DS-AM-302 (4.6 mmID x l50 awake L), mobile phase: 0.1. 1¾; TFA / acet nitrile = 93/7, flow rate: 1 ml / min, detection wavelength: 240 nm, Injection volume: 15 ul

The bulk powder is first dissolved by adding lOml physiological saline to the vial, and then subjected to two 10-fold dilutions with distilled water for injection for quantitative determination. After dissolving in 5-10 ml of physiological saline, leave at room temperature for 1 hour and measure turbidity. The measurement is performed at 600MB.

6. Store the vial enclosing the bulk powder in a storage at the specified temperature and remove it after storage for the specified period. Measure the content and turbidity in the same manner as above. For content measurement, use the freeze-dried product for the calibration curve, and calculate the residual rate with the initial content as 100%.

(Result)

(Table 7)

The crystals of the present invention, particularly the dihydrochloride and dihydrobromide, exhibited higher stability Δfe than the sulfate crystals. Formulation Example 1

An injection is prepared by dissolving the dihydrochloride of compound (I) obtained in Example 1 and a base for adjusting pH in distilled water.

Formulation Example 2

A dihydrobromide salt of the compound (I) obtained in Example 2 and a base for adjusting pH are dissolved in distilled water in a vial, and lyophilized to prepare an injection.

Formulation Example 3

The dinitrate of compound (I) obtained in Example 3 and a base for adjusting pH are powder-filled to prepare an injection. Industrial applicability

The crystals of various inorganic acid salts of the septum compound (I) or solvates thereof of the present invention are excellent in solubility, storage stability, handleability in formulation, etc., and can be used particularly as an active ingredient of an injection. . Further, according to the production method of the present invention, these crystals can be industrially produced efficiently with high yield and high purity.

Claims

Claim formula:

2. The crystal according to claim 1, which is a dihydrochloride or a hydrate thereof.

3. The crystal according to claim 1, which is a 0.5 to 5 hydrate of dihydrochloride.

4. The crystal according to claim 1, which is a pentahydrate of dihydrochloride.

5. In the powder X-ray diffraction pattern, the plane spacing (d) is 4.99, 4.89, 4.67, 4.57, 4.45,

4. A crystal of the dihydrochloride salt or a hydrate thereof according to claim 1, showing a main peak around 4.18, 3.70, 3.58, 3.43, 3.39 and 3.34 (unit: A).

6. The crystal according to claim 5, which is a pentahydrate of dihydrochloride.

The crystal according to claim 1, which is a hemihydrate of 7-2 dihydrochloride.

8. In the powder X-ray diffraction pattern, the plane spacing (d) is 9.52, 5.10, 4.49, 3.87, 3.66, 3.56,

The crystal of the dihydrochloride or a hydrate thereof according to claim 1, which shows a main peak near 3.47, 3.40, 3.37, 3.30, 3.24, 3.18, 3.11, and 2.79 (unit: A).

9. The crystal according to claim 8, which is a hemihydrate of dihydrochloride.

10. The crystal according to claim 1, which is a hydrobromide salt or a hydrate thereof.

11. The crystal of claim 1, which is 0.5 to 5 hydrate of dihydrobromide.

12. The crystal of claim 1, which is tetrahydrate of dihydrobromide.

13. The powder according to claim 1, wherein in the powder X-ray diffraction pattern, the interplanar spacing (d) shows a main peak around 5.29, 4.45, 4.28, 3.65, 3.52, 3.42, 3.35 and 3.12 (unit: A). Crystals of hydrobromide or its hydrate.

14. The crystal according to claim 13, which is tetrahydrate of 1.2 hydrobromide.

15. The crystal of claim 1, which is a hemihydrate of dihydrobromide.

The crystal according to claim 1, which is 16.2 nitrate or a hydrate thereof.

17. The crystal according to claim 1, which is 0.5 to pentahydrate of dinitrate.

18. The crystal of claim 1, which is trihydrate of dinitrate.

1 9. In the powder X-ray diffraction pattern, the plane spacing (d) was 5.34, 5.13, 5.01, 4.83, 4.64,

2. The crystal of the dinitrate or its hydrate according to claim 1, which shows a main peak around 4.57, 4.43, 4.16, 4.06, 3.71, 3.40, 3.39, 3.33 (unit: A).

20. The crystal of claim 19 which is trihydrate of dinitrate.

2. The crystal of claim 1, which is a 0.5 hydrate of 21.2 nitrate.

22. In the powder X-ray diffraction pattern, the interplanar spacing (d) was 9.60, 9.24, 6.89, 5.15, 5.05, 4.52,

2. The crystal of dinitrate or a hydrate thereof according to claim 1, which shows a main peak near 4.05, 3.98, 3.94, 3.68, 3.51, 3.33, 3.25, 2.89, and 2.88 (unit: A).

23. The crystal of claim 22, which is a hemihydrate of dinitrate.

24. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 23.

25. The pharmaceutical composition according to claim 24, which is an antibacterial agent and / or an injection.

26. A method for preventing or treating bacterial infection, which comprises administering the crystal according to any one of claims 1 to 23.

27. Use of a crystal according to any one of claims 1 to 23 for the manufacture of a prophylactic or therapeutic agent for a bacterial infection.

28. The crystal of an acid addition salt of compound (I) or a solvate thereof according to claim 1, characterized in that a monosulfate of compound (I) is mixed with an acid, and then alcohol is added for precipitation. Manufacturing method.

29. Parium chloride, barium nitrate, barium bromide, or parium hydroxide is added to an aqueous solution of compound (I) monosulfate in the presence of an acid, if necessary, to precipitate and remove barium sulfate. 2. The compound according to claim 1, wherein an alcohol is added to the compound.

A method for producing a crystal of an acid addition salt of (I) or a solvate thereof. '