JPH01199977A - Crystal of cephalosporin derivative, production thereof and drug composition comprising said crystal as active ingredient - Google Patents

Abstract

NEW MATERIAL:Crystal of (6R,7R)-7-[ 2-( 2-amino-4-thiazolyl )-2-[ Z-[( 2- carboxy-4,5-dihydroxyp henyl )methyl ]oxyimino ]acetamido ]-3-[ (2-carboxy-5- methyl-S-triazol o[ 1,5-a ]pyrimidin-7-yl )thiomethyl ]-8-oxo-5-thia-1-azabicyclo[ 4,2,0 ]oct-2-enecarboxylic acid shown by the formula and a nontoxic salt thereof in a solvent form. EXAMPLE:Crystal of a compound shown by formula-formic acid solvate. USE:An active component for a drug composition. Being characterized by specific infrared absorption spectrum or specific diffraction pattern of powder X-ray crystal diffraction, having no absorbing properties, stable even in long-term preservation and useful for infectious diseases. PREPARATION:A compound shown by the formula or a nontoxic salt thereof is dissolved in a solvent such as water or formic acid at -40-80 deg.C and crystal is precipitated to give crystal of the compound shown by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to stable crystals of cephalosporin derivatives, processes for their production, and pharmaceutical compositions containing them.

rPrior art" Compound represented by (6R,7R)-7-[2-(2-
amino-4-thiazolyl')-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5
-Methyl-8-triazolo[1,5-a]pyrimidine-
7-yl)thiomethyl]-8-oxo-5-thia-1-
Azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid is a powerful antibacterial agent with a wide range of effects against both Durum-positive and Durum-negative bacteria, as described in JP-A-63-132893. It is an antibiotic that exhibits excellent antibacterial activity, especially against Pseudomonas aeruginosa, and is also highly safe. Pseudomonas aeruginosa is frequently isolated as a causative agent of refractory infections, and in recent years there has been a desire for the development of cephalosporin antibiotics that have strong antibacterial activity against this bacterium and are highly safe. From this point of view, the above-mentioned compounds are particularly important drugs for the treatment of infectious diseases.

"Problems to be Solved by the Invention" The compound represented by the general formula (1) described in JP-A No. 63-132893 is a medically important compound as described above, but it is an amorphous trisodium salt. It is solid. Although this product has excellent solubility required for injections, it is highly hygroscopic at room temperature and difficult to handle as a bulk powder. Furthermore, the stability as a bulk powder is not always sufficient and there is a problem.

Means for Solving the Problems The present inventors have conducted extensive research to solve the problems described above, and as a result, the present inventors have found that a solution expressed by the general formula (1) (6R
,7R) -7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methylcooximino]acetamide]
-3-[(2-carboxy-5-methyl-8-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]
-8-oxo-5-thia-1-azabicyclo[4,2°0]oct-2-ene-2-carboxylic acid crystals in solvated (including hydrated) form with high purity and high yield. I found a way to get it.

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[( 2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl2-8-oxo-5-thia-1-azabicyclo[4,
The hydrated crystal of 2,O]oct-2-ene-2-carboxylic acid exhibits the following characteristic absorption and diffraction patterns in infrared absorption spectra and powder XuI crystal diffraction.

IR spectrum (KBr, cm-'): νmax
3600-2200, 3275, 1769, 1652.
1596.1542.1521.1519.1307.
1272.1190.1160, 1103.1064.
1028,964,901,854,795,770 powder xl crystal diffraction pattern; (d spacing (in angstroms) and percentage intensity): 19, 11 (5
5), 14.34 (11), 9.48 (48)
, 8.73 (13), 7.19 (37), 6.
27 (82), 5.73 (58), 5.34 (20),
5.21 (28), 4.78 (77), 4.53 (42
), 4.26 (25), 3.97 (100), 3.79
(74), 3°66 (44), 3.56 (73), 3.
36 (47), 3.22 (22), 3.15 (13),
3°11 (26), 2.85 (28), 2.
75 (12), 2.62 (13), 2.49 (
10), 2゜12(13), 1.98(16) The hydrated crystal of the compound represented by formula (1) is generally a cephalosporin, a salt thereof, or a solvate thereof. It can be manufactured from things. That is, (6R,7R)-7-[2-(2-amino-4-thiazolyl')-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl) represented by general formula (1) ) methyl]oximino]acetamide]-3-[(2-carboxy-5-methyl-5-)riazolo[1,,5-alpyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo [4
, 2,0] oct-2-ene-2-carboxylic acid, its trisodium salt, trifluoroacetate, etc., in a suitable solvent, or after making them into solvates, such as formic acid, acetic acid, etc. , in a suitable solvent, from -40°C to 80°C.
℃1 Preferably in the temperature range of 0°C to 50''C, and if desired, the pH can be adjusted to 1.0 to 4.0.

In order to achieve this pH, it is also possible to coexist with an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or an organic acid such as formic acid or acetic acid for crystallization. Furthermore, if desired, crystallization can be carried out using a crystalline substance as a seed, and recrystallization can be carried out in a suitable acidic solvent in a conventional manner.

Suitable solvents include water, which has a large dielectric constant and dipole moment, lower aliphatic alcohols such as methanol, ethanol, and isopropanol, lower aliphatic carboxylic acids such as carbonic acid, formic acid, and acetic acid, and N,N-dimethyl. Examples include amide solvents such as formamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and ether solvents such as monoglyme, diglyme, and tetrahydrofuran.

It is also possible to use mixed solvents such as 50% acetone-water and 30% methanol-water.

Non-toxic salts that can be formed by reaction of the carboxyl group of the compound represented by general formula (I) include, for example, inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts). ), amino acid salts (e.g. lysine and arginine salts)
, organic base salts (e.g. brocaine, phenylethylbenzylamine, dibenzylethylenediamine, jetanolamine and N-methylglucosamine salts), with the sodium salt being particularly preferred; other non-toxic salt derivatives include, e.g. hydrochloric acid, Included are acid addition salts formed with hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, and trifluoroacetic acid.

(6R,7R) -7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[( 2-carboxy-5-methyl-8-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,
The formic acid solvate thereof is particularly preferred as the compound of general formula (I) used for the preparation of the crystalline hydrated form of 2,0]oct-2-ene-2-carboxylic acid.

The formic acid solvate of the compound of general formula (1) can be obtained as a crystal, and the formic acid solvate of the compound of general formula (I) and its production method are also included in the present invention.

(6R,7Ft)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide: 1-3-[ (2-carboxy-5-methyl-5-)
Riazolo[L5-a]pyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,
Crystals of formic acid solvate of 2,0]oct-2-ene-2-carboxylic acid exhibit the following characteristic absorption in infrared absorption spectrum and powder X-ray diffraction.

IR spectrum (Nujol, cm-'v max3
600-2200 (wide) t 3269.1770.1
654.1596.1517.1509.1303,1
188, 1159, 1101, 1061, 1025, 9
62,904,853°794.770 Powder X-ray diffraction pattern; (d-spacing (in Angstroms) and percentage intensity): 18.87 (39)
, 10.01 (22), 9.17 (22), 8.25 (
20),? . 54 (23), 6.18 (40), 5.7
1 (22), 5.05 (34), 4.77 (41), 4
．． 53 (55), 4.24 (42), 3.97 (57)
, 3.77 (100), 3.63 (52), 3゜51
(88), 3.32 (60), 3.12 (4
8), 3.00 (28), 2.76 (32
), 2゜67(27), 2.52(32),
2.49 (31), 2.47 (29), 2.3
1(26), 2゜23(25), 2.03(21) (6R,7R)-7-[2-(2-amino-4-thiazolyl')-2-[Z-[(2-carboxy -4,5-dihydroxyphenyl)methyl]oximinocoacetamide]-3-[(2-carboxy-5-methyl-8-triazolo[1,δ-a]pyrimidin-7-yl)thiomethyl]-8- Oxo-5-thia-1-azabicyclo[4,
Crystals of the formic acid solvate of 2,0-cooct-2-ene-2-carboxylic acid are generally prepared from the cephalosporin, its base salt (e.g. trisodium salt), or acid addition salt (e.g. hydrochloride, trifluoroacetic acid salt). salt). That is, (6R,7FL)-7- represented by general formula (1)
[2-(2-amino-4-thiazolyl)-2-[Z-[
(2-carboxy-4゜5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5-methyl-5-)riazolo[1,5-a]pyrimidin-7-yl)thiomethyl] -8-Oxo5-
Thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid, its trisodium salt, or a salt such as trifluoroacetate is dissolved in formic acid, and
'Crystallization is carried out in the range of C. Crystallization can be carried out by adding water to the reaction system, and if necessary, an acid such as hydrochloric acid or seeds can be added to make crystallization more efficient.

Crystals of the compounds of the invention exhibit a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative bacteria, including many β-lactamase producing strains. It shows particularly strong antibacterial activity against Pseudomonas aeruginosa.

Crystals of these compounds also have high stability towards β-lactamases produced by a range of Gram-negative and -negative bacteria.

Crystals of the compounds of the present invention can be used to treat various diseases caused by pathogenic bacteria in humans and/or animals, such as respiratory infections and urinary tract infections. Crystals of the compounds of the invention, like other antibiotics, can be formulated and administered in any convenient manner, and therefore the invention includes crystals for use in treating human and/or animal diseases. Also included within the scope are pharmaceutical compositions containing crystals of compatible compounds of the invention. Such compositions can be subjected to conventional use with any required pharmaceutical carriers or excipients.

Crystalline compounds of the present invention can be formulated for injection and presented in unit dosage form, in ampoules, or in vials, with the addition of preservatives if necessary. These compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous carriers and may also contain formulation agents such as suspending, stabilizing, and/or dispersing agents. It can also contain. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable solvent, eg sterile, pyrodiene-free, before use.

If desired, such powder formulations may be used to improve the aqueous solubility of the active ingredient and/or to ensure that the pH of the aqueous formulation obtained when the powder is reconstituted with water is physiologically acceptable. A suitable non-toxic base may also be included. Alternatively, the base may be present in the water that reconstitutes the powder. The base can be, for example, an inorganic base such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base such as lysine or lysine acetate.

The formulations may also be presented in forms suitable for absorption by the gastrointestinal tract, such as tablets, capsules, syrups, or suspensions for oral administration, and suppositories.

These compositions may contain 0.1% or more of active ingredient, for example from 0.1 to 99%, depending on the method of administration. When the composition consists of dosage units, each unit preferably contains 1
00 to 3000 mg, for example 200 to 2000 mg of active ingredient. The daily dose for the treatment of adults varies depending on the nature of the infection and the route and frequency of administration.
．． Intravenous or intramuscular administration using 0.1 to 10 g, preferably 0.1 to 5 g of active ingredient per day may be employed. Oral administration is also possible. It will be appreciated that smaller dosage units and daily doses may be desirable in some circumstances, such as in the treatment of neonates.

Crystals of the compounds according to the invention can be administered in combination with other therapeutic agents such as antibiotics, such as penicillins, cephalosporins or other β-lactam compounds.

"Examples" Examples of the present invention are shown below, but the present invention is not limited to the following examples.

Example 1 (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamide]-3 -[(2-carboxy-5-methyl-5-)riazolo[1,5-mycopyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,2
,0] Preparation of crystals of oct-2-ene-2-carboxylic acid-formic acid solvate.

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[( 2-Carboxy-5-methyl-s-triazolo[1,5mycopyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,2
, 0 Cooct-2-ene-2-carboxylic acid trifluoroacetate (3.0 g) was dissolved in 15 ml of formic acid at room temperature.

15 ml of water was added to this and stirred at room temperature for 1 hour.

Further, 5 ml of water was added, and the mixture was stirred at room temperature for 30 minutes, and crystal seeds were added. 10 ml of water was added and stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and washed with 20 ml of water.

It was air-dried at room temperature to obtain 1.95 g of the listed crystals.

IR (nujol, cm-1); 3600-2200,
3269.1770.1854.1596, 1517.
1509.1303.1188.1159.1101.
1061,1025,962,904.853.794
．． 77ONMR (DMSO-d6.ppm);9.
61 (d, IH, J=8Hz), 9.44 (
brs.

IH), 9.18 (brs, IH), 8.
12 (s, HCOOR), 7.40 (st I
H), 7°35 (s, IH), 7.17 (
s, 2H), 6.89 (s, IH), 6
．． 75 (slH), 5.88 (dd, IH, J
=8.4Hz), 5.39(s, 2H), 5
．． 20 (d, IH, J=4Hz).

4.43 (s, 2H), 3.70 (ABq, 2H), 2
．． 62(s, 3H) powder X-ray crystal diffraction pattern; (d-spacing (in Angstroms) and percentage intensity) = 18.87(39), 10.01(22), 9.1
7 (22), 8.25 (20), 7.54 (23), 6
．． 18 (40), 5.71 (22), 5.05 (34)
, 4.77 (41), 4.53 (55), 4.24
(42), 3.97 (57), 3.77(
100), 3.63 (52), 3゜51 (
88), 3.32 (60), 3.12 (48)
, 3.00 (28) , 2.76 (32)
, 2゜67 (27), 2.52 (32), 2.49 (
31), 2.47 (29), 2.31 (26), 2゜2
3(25), 2.03(21) Example 2 (6R,7R) -7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5- dihydroxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a-copyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo [4
, 2,0] Preparation of crystals of oct-2-ene-2-carboxylic acid-formic acid solvate.

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methylcooximino]acetamide]-3-[ (2-carboxy-5-methyl-8-triazolo[1,5-mycopyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,
1.1 g of trisodium 2,01 oct-2-ene-2-carboxylic acid was dissolved in 3 ml of water, and 1.5 ml of formic acid and 2 ml of water were added. This was stirred at room temperature for 5 minutes and 5 ml of water was added. This solution was stirred for 30 minutes under water cooling, and the precipitated crystals were collected by filtration and washed with 5 ml of water. The obtained crystals were dried under reduced pressure in a desiccator to obtain 0.89 g of the indicated crystals.

IR (nujol, cm-'); 3600-2200,
3255, 1764.1701.1653, 1597.
1542.1517.1305.1268.1220.
1203.1186.1172, 1157.1103.
1065.1020.962.907.852.795
．． 771NMR (DMSO-d6.ppm);9.
61 (d, IH, J=8Hz), 9.44 (
brs.

IH), 9.18 (brs, IH), 8.1
2 (s, HCOOH), 7.40 (s, IH)
, 7゜35 (s, IH) , 7.17 (s, 2
H), 6.89(s, IH), 6.75(s
lH), 5.88 (dd, IH, J=8.4H
z), 5.39 (s, 2H), 5.20
(d, IH, J=4Hz).

4.43 (s, 2H), 3.70 (ABq, 2H), 2
．． 62(s, 3H) powder X-ray crystal diffraction pattern; (d-spacing (in Angstroms) and percentage intensity) 2 15.94 (29), 8.48 (32),
7.10 (37), 5.90 (45), 4
．． 84 (42), 4.58 (44), 4.38
(61), 3.83 (75), 3.66 (1
00), 3.53 (74), 3.42 (99)
, 3.24 (80) , 3.05 (62) ,
2.81 (41), 2.70 (45), 2.47
(4B), 2.27(41), 2.20(39) Example 3 (6R,7R)-7-[2-(2-amino-4-thiazolyl')-2-[Z-[(2 -carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5-methyl-8-triazolo[1,5-mycopyrimidin-7-yl)thiomethyl]-8-oxo 5-thia-1-azabicyclo[4,
Preparation of crystals of 2,01 oct-2-ene-2-carboxylic acid permanent product.

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[( 2-Carboxy-5-methyl-8-triazolo[1,5-a cobyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,2
, O-oct-2-ene-2-carboxylic acid trifluoroacetate (3.0 g) was dissolved in 15 ml of formic acid at room temperature.

15 ml of water was added to this and stirred at room temperature for 1 hour.

Further, 5 ml of water was added, stirred at room temperature for 30 minutes, and seed crystals were added. 10 ml of water was added and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed with 20 ml of water. Additionally, 30ml of water
The crystals were washed with stirring and filtered. Air-dry at room temperature, crystal 1
．． 85g was obtained.

IR (KBr, cm-”); 3600-2200
(wide), 3261.1768, 1653, 1595
．． 1517.1509.1305.1269.1188
．． 1158.1103.1063, 1024.962.
903.853.795.77ONMR(DMSO-d
6. ppm) ;9.54 (d, IH, J=8H
z), 7.41 (s, IH), 7.36
(s, IK), 6.89 (s, IH), 7
．． 4-6.9 (brs, 2H), 6.76 (s,
IH), 5.81 (dd, IH, J=8.5H
z), 5.39(s, 2H), 5.21(d
, IH, J=5Hz), 4.43(brs, 2
H), 4.1 (brs, 2H), 2.6(s
.

3H) Powder X-ray crystal diffraction pattern; (d-spacing (in Angstroms) and percentage intensity): 18.95 (4
4), 9.48 (27), 8.23 (12), 7.47
(21), 7.14 (21) 6.21 (60),
5.70 (33), 5.20 (16), 4.7
5 (88), 4, 51 (61).

4.22 (36), 3.95 (74), 3.
77 (100), 3.65 (17), 3.5
0 (63), 3.36 (31)t 3.22(1
3), 3.10 (41), 2.84 (16)
, 2.75 Example 4 (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino] acetamide]-3-[(2-carboxy-5-methyl-s-trifuzolo[1+ 5 acobyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,
Preparation of crystals of 2,0]oct-2-ene-2-carboxylic acid hydrate.

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[( 2-carboxy-5-methyl-5-)riazolo[1,5-mycopyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,2
, O-oct-2-ene-2-carboxylic acid trisodium salt (1.1 g) was dissolved in 3 ml of water, and 1.5 ml of formic acid was added. This was stirred at room temperature for 5 minutes and 5 ml of water was added. This solution was stirred with water cooling for 30 minutes, and the precipitated crystals were collected by filtration and washed once with 2 ml of water and once with 1 ml. It was dissolved in 5 ml of the obtained crystalline formic acid and 5 ml of water was added. 10 ml of water was added and stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and washed with 20 ml of water. The crystals were further stirred and washed with 30 ml of water, and the crystals were collected by filtration. It was air-dried at room temperature to obtain 0.89 g of the title crystal.

IR (KBr, cm-1); 3600-2200 (wide), 3275.1769, 1652, 1596.15
42.1521.1519.1307.1272.11
90.1160.1103, 1064.1026.96
4.901,854,795,77ONMR(DMSO
-d6. ppm); 9.54 (d, IH, J=8Hz)
, 7.41 (s, IH) , 7.36 (s, IH
), 6.89 (s, IH), 7.4-6.
9 (brs, 2H), 6.76 (s, 1H)
, 5.81 (dd, IH, J=8.5Hz)
, 5.39(s, 2)T) , 5.21(d,
IH, J=5Hz), 4.43 (brs, 2H
), 4.1 (brs, 2H), 2.6 (
s.

3H) Powder X-ray crystal diffraction pattern; (d-spacing (in Angstroms) and percentage intensity): 19, 11 (
55), 14.34 (11), 9.48 (48
), 3.73 (13), 7.19 (37),
6.27 (82), 5.73 (58), 5.3
4 (20), 5.21 (28), 4.78
(77), 4.53 (42), 4.26 (25), 3.
97 (100), 3.79 (74), 3°66 (44)
, 3.56 (73) , 3.36 (47) ,
3.22 (22), 3.15 (13), 3゜11 (26), 2.85 (28), 2.75
(12), 2.62 (13), 2.49 (1
0), 2゜12(13), 1.98(16) Example 5 (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy -4,5-dihydroxyphenyl)methyl]oximinocoacetamide]-3-[(2-carboxy-5-methyl-5-)riazolo[1,5-a-copyrimidin-7-yl)thiomethyl]-8- Oxo-5-thia-1-azabicyclo[4,
Preparation of crystals of 2,0]oct-2-ene-2-carboxylic acid hydrate.

(6R27R)- obtained in Example 1 or Example 2
7-[2-(2-amino-4-thiazolyl') -2-
[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(
2-carboxy-5-methyl-s-)riazolo[1,
5-mycopyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-7zabicyclo[4,2,0]oct-2-ene-2-carboxylic acid-formic acid solvate 1.85
g was dissolved in 10 ml of formic acid. 12 ml of water was added to this and stirred at room temperature for 30 minutes. 10 ml of water was added to this, and the mixture was further stirred for 1 hour. The precipitated crystals were collected by filtration and washed with 30 ml of water. It was air-dried at room temperature to obtain 0.89 g of the title crystal.

IR (KBr, cm-1); 3600-2200 (wide), 3275.1769, 1652, 1596.154
2.1521.1519.1307.1272.119
0.1160.1103, 1064.1026.964
．． 901, 854.795.77ONMR (DMSO
-d6. ppm) ;9.54 (d, IL J=
8Hz), 7.41 (s, IH), 7.3
6 (s, IH), 6.89 (s, IH)
, 7.4-6.9 (brs, 2H), 6.76
(s, IH), 5.81 (dd, IH, J
=8.5Hz), 5.39(s, 2H), 5.
21 (d, IH, J=5Hz), 4.43 (br
s, 2H), 4.1 (brs, 2H), 2.6
(s.

3H) Powder X-ray crystal diffraction pattern; (d-spacing (in Angstroms) and percentage intensity): 19.11 (
55), 14.34 (11), 9.48 (48
), 8.73 (13), 7.19 (37),
6.27 (82), 5.73 (58), 5.
34 (20), 5.21 (28), 4.78
(77), 4.53 (42), 4.26 (
25), 3.97 (100), 3.79 (7
4), 3°66 (44), 3.56 (73), 3.3
6 (47), 3.22 (22), 3.15 (13), 3
゜11 (26), 2.85 (28), 2.75 (12)
, 2.62 (13), 2.49 (10), 2°12 (1
3), 1.98 (16) Next, Examples will be described regarding preparations containing crystals of the cephalosporin derivative of the present invention.

Example 6 Method for producing dry injections for parenteral administration (6R, 7R)
-7-[2-(2-amino-4-thiazolyl)-2-[
Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyiminocoacetamide]-3-[(2
-carboxy-5-methyl-5-)riazolo[1,5-
mycopyrimidin-7-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo[4,2,0]octo-
2-ene-2-carboxylic acid hydrate crystal powder 1.1
g*8 equivalents of sodium bicarbonate were powder-filled into a 5 ml vial. This is sealed in a conventional manner to obtain a dry injection.

Example 7 Method for manufacturing tablets for oral administration (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl) ) methyl]oximino]acetamide]-3-[(2-carboxy-5-methyl-5-)riazolo[1,5-a]pyrimidin-7-yl)thiomethylco8-oxo5-thia-1-azabicyclo[4 ,2
,0] Oct-2-ene-2-carboxylic acid hydrate crystal powder 250 mg + lactose 100 mg
t starch 30 mg * polyvinylpyrrolidone 1
Using 0 mg, 9 was made into granules using a conventional method. Add and mix starch somg + magnesium stearate 5mg to this granule, and compress this.

Each tablet weighed 425 mg.

Example 8 Method for manufacturing gelatin capsules for oral administration (6R,
7R)-7-[2-(2-amino-4-thiazolyl)-
2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oximino]acetamide]-3-
[(2-carboxy-5-methyl-s-triazolo[
1,5-a]pyrimidin-7-yl)thiomethyl]-8
-Oxo-5-thia-1-azabicyclo[4,2,0]
Oct-2-ene-2-carboxylic acid hydrate crystal powder 250 mg + water-soluble polyvinylpyrrolidone 15
m g t mannitol 15 m g r talc 15
mg and 5 mg of magnesium stearate were uniformly mixed to form gelatin capsules each weighing 300 mg.

"Effects of the Invention" As is clear from the above, the present invention is a crystal of a cephalosporin derivative that is non-hygroscopic, extremely stable for long-term storage, and extremely useful medically. Since crystals of cephalosporin derivatives, which are extremely stable in storage and extremely useful medically, can be obtained with high purity and high yield through industrially easy operations, the present invention is extremely useful in the medical and pharmaceutical industries. be.

Claims (11)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (6R,7R)-7-[2-(2-amino-) represented by (I)
4-thiazolyl)-2-[Z-[(2-carboxy-4
,5-dihydroxyphenyl)methyl]oximino]
acetamide]-3-[(2-carboxy-5-methyl-
s-triazolo[1,5-a]pyrimidin-7-yl)
A crystalline solvated form of [thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and its non-toxic salts. (2) The crystal according to claim 1, wherein the solvation is hydration. (3) The following absorption bands in the infrared absorption spectrum; (KBr, cm^-^1) 3600-2200 (wide), 3275, 1769, 1652, 1596, 15
42, 1521, 1519, 1307, 1272, 11
90, 1160, 1103, 1064, 1026, 96
3. A crystal according to claim 2, characterized in that it contains 4,901,854,795,770. (4) The following diffraction pattern in powder X-ray crystal diffraction; (
d-spacing (in Angstroms and percentage intensity): 19.11 (55), 14.34 (11), 9
．． 48 (48), 8.73 (13), 7.19 (37)
, 6.27 (82), 5.73 (58), 5.34 (2
0), 5.21 (28), 4.78 (77), 4.53
(42), 4.26 (25), 3.97 (100), 3
．． 79 (74), 3.66 (44), 3.56 (73)
, 3.36 (47), 3.22 (22), 3.15 (1
3), 3.11 (26), 2.85 (28), 2.75
(12), 2.62 (13), 2.49 (10), 2.
12 (13), 1.98 (16). (5) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) represented by (6R,7R)-7-[2-(2-amino-
4-thiazolyl)-2-[Z-[(2-carboxy-4
,5-dihydroxyphenyl)methyl]oximino]
acetamide]-3-[(2-carboxy-5-methyl-
s-triazolo[1,5-a]pyrimidin-7-yl)
thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
It is characterized by forming a solution of the non-toxic salt or a solvate thereof, then adding water to the solution, and precipitating the crystals according to claim 2, claim 3, or claim 4 therefrom. Production method. (6) In the method for producing crystals according to claim 5, water alone;
Alternatively, using an aqueous solution of water and lower aliphatic alcohols such as acetone, methanol, and ethanol, and lower fatty acids such as carbonic acid, formic acid, and acetic acid, the general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I ) (6R,7R)-7-[2-(2-amino-
4-thiazolyl)-2-[Z-[(2-carboxy-4
,5-dihydroxyphenyl)methyl]oximino]
acetamide]-3-[(2-carboxy-5-methyl-
s-triazolo[1,5-a]pyrimidin-7-yl)
thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
A method of precipitating crystals by forming an aqueous solution of the non-toxic salt or solvate thereof and adjusting the pH of the solution to 1.0 to 4.0. (7) The crystal according to claim 1 in a form solvated with formic acid. (8) The following absorption bands in the infrared absorption spectrum; (KBr, cm^-^1) 3600-2200 (broad), 3269, 1770, 1654, 1596, 15
17, 1509, 1303, 1188, 1159, 11
01, 1061, 1025, 962, 904, 853,
8. Crystal according to claim 7, characterized in that it contains 794,770. (9) Powder X-ray crystal diffraction shows the following diffraction pattern; (
d-spacing (in Angstroms and percentage intensity): 18.87 (39), 10.01 (22), 9
．． 17 (22), 8.25 (20), 7.54 (23)
, 6.18 (40), 5.71 (22), 5.05 (3
4), 4.77 (41), 4.53 (55), 4.24
(42), 3.97 (57), 3.77 (100), 3
．． 63 (52), 3.51 (88), 3.32 (60)
, 3.12 (48), 3.00 (28), 2.76 (3
2), 2.67 (27), 2.52 (32), 2.49
(31), 2.47 (29), 2.31 (26), 2.
8. Crystal according to claim 7, characterized by: 23(25), 20.3(21). (10) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (6R,7R)-7-[2-(2-amino-) represented by (I)
4-thiazolyl)-2-[Z-[(2-carboxy-4
,5-dihydroxyphenyl)methyl]oximino]
acetamide]-3-[(2-carboxy-5-methyl-
s-triazolo[1,5-a]pyrimidin-7-yl)
thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
Forming a solution of the non-toxic salt or solvate thereof in formic acid, from which the non-toxic salt or solvate thereof is prepared.
A manufacturing method characterized by precipitating the crystals described above or adding water to the solution to precipitate the crystals according to claim 7, claim 8, or claim 9. (11) As an active ingredient, (6R,7R)-7-[2-(2-amino-
4-thiazolyl)-2-[Z-[(2-carboxy-4
,5-dihydroxyphenyl)methyl]oximino]
acetamide]-3-[(2-carboxy-5-methyl-
s-triazolo[1,5-a]pyrimidin-7-yl)
thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and its non-toxic salts in a solvated form. A pharmaceutical composition characterized by: