CA1243297A - Crystalline modification of ceftazidim - Google Patents
Crystalline modification of ceftazidimInfo
- Publication number
- CA1243297A CA1243297A CA000452042A CA452042A CA1243297A CA 1243297 A CA1243297 A CA 1243297A CA 000452042 A CA000452042 A CA 000452042A CA 452042 A CA452042 A CA 452042A CA 1243297 A CA1243297 A CA 1243297A
- Authority
- CA
- Canada
- Prior art keywords
- crystalline
- carboxyprop
- aminothiazol
- cephem
- carboxylate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Abstract of the disclosure:
Crystalline (6R,7R)-7-CtZ)-2-t2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oximino)acetamido]-3-(1-pyr;-diniummethyl)-3-cephem-4-carboxylate x 1.5 mol water and a process for its preparation, a pharmaceutical formula-tion active against bacterial infections which contains this compound and a process for the preparation of the formulation and the use of this compound for controlling bacterial infections.
Crystalline (6R,7R)-7-CtZ)-2-t2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oximino)acetamido]-3-(1-pyr;-diniummethyl)-3-cephem-4-carboxylate x 1.5 mol water and a process for its preparation, a pharmaceutical formula-tion active against bacterial infections which contains this compound and a process for the preparation of the formulation and the use of this compound for controlling bacterial infections.
Description
~z43z9~7 toR,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(2-carboxyprop-2-ox;m;no)acetam;do~-3-(1-pyrid;n;ummethyl)-3-cephem-4-carboxylate (ceftaz;d;m~ ;s a cephalospor;n ant;b;ot;c of the 3rd generat;on wh;ch has pronounced eff;cacy for 6ram-negat;ve pathogens, ;nclud;ng pseudo-monas spec;es. The pentahydrate of th;s compound (cf.
German Offenlegungsschr;ft 3,037,102) has h;therto been the only crystall;ne form wh;ch ;s well su;ted for parenteral use.
It is known that the stab;l;ty of cephalosporins ;s l;mited and that they readily decompose on storage.
The cause of this ;s the h;gh sensitivity to hydrolysis of the ~-lactam ring ~h;ch can even react slowly w;th water bound in the crystal latt;cs when the molecule ;s exposed to heat stress or is sto'red for a prolonged per;od at room temperature. Thus ;t is very important to employ the most stable crystall;ne form poss;ble for med;cal use of a cephalosporin antibiotic.
It has now been found that ceftaz;d;m can be con-verted ;nto a new crystall;ne mod;f;cation which is dis-t;ngu;shed from the pentahydrate by ;ncreased stab;l;ty to heat and ;s part;cularly ~ell su;ted for a parenteral formulat;on.
Thus the ;nvent;on relates to a crystall;ne ceftaz;d;m x 1.5 mol water~ ;ts'pharmaceutical formula-t;ons, and a process for ;ts preparat;on wh;ch compr;ses rehydrat;ng anhydrous crystalline ceftazid;m in mo;st ~24~t297 a;r until the indicated amount of water has been absorbed.
The crystall;ne mod;f;cation accord;ng to the invention has a characteristic Debye-Scherrer diagram ~Table 1) wh;ch proves the presence of a new crystalline form having new phys;cal and chemicaL properties.
The water content of ~he ceftazidim crystall;ne mod;fication according to the invention can vary by 0.2 to 0.4 mol, depend;ng on the atmospheric humidity under which the samples are manipulated and investigated, without any change in the crystalline modification bein observed.
The anhydrous crystalline form ~hich can be employed as start;ng mater;al can be obtained as cla;med 5 in Canadian Patent Application No. 452,043 by dehydrat;on of a crystall;ne ceftazidim hydrate, preferably the pentahydrate, to constant ~e;ght~
The absorption of water can be carried out using a;r under normal amb;en~ condit;ons or hav;ng an increased moisture content, such as, for example, 50 to 80Z relative atmospher;c humidity. The mo;sture content of the a;r can also be art;fic;ally increased in a known manner, for example by prev;ously mix;ng with ~ater vapor.
The desired amount of water in the crystals is followed by weight checks and, after achieving complete conversion of the crystals into a hydrate containing 1.5 mol of water, absorption is terminated.
As a rule, rehydration is carried out at room ~ , , `
L3;;~9~
~, temperature, bu~ it can also take place at elevated tfor example 40C) or reduced temperatures tfor example 1 0 C ) The time for the rehydration depends, in par-S ticular, on the particle size of the starting material, the thickness of the layer of material and the external conditions, such as, for example, the atmospheric humi-dity and the temperature. Thus, for example, it can be bet~een several hours and days.
The crystalline mod;fication according to the invention exhibits a higher stability than ceftazidim pentahydrate on storage of the samples under heat stress, and is thus ~ore suited for medical use.
The compound accord;ng to the invention is a valuable antibiotic ~hich is suited for controlling Gram-positive and, in particular, 6ram-negative ;nfections (cf. German Offenlegungsschrift 2,921,316).
Thus, the invention also relates to pharmaceuti-cal formulations ~hich contain the compound according to the invention, such as, for examp~e, solutions, suspen-sions or emulsions in oily or aqueous vehicles.
The compound according to the invention can be used as such or combined ~ith auxiliaries customarily employed in therapy, such as, for example, formulating agents, solvents, suspending agents and/or dispersants.
It ;s also possible for the active compound, before being used, to be present in the formulation in the form of a powder, for example, for dissoLution in, for ex-ample, sterile and pyrogen-free ~ater. In order to ,`
prepare aqueous solutions, the act;ve compound is advan-tageously dissolved by the addition of a basic aux;liary, such as, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium car-bonate, calcium carbonate, magnesiurn carbonate, tri-hydroxymethylmethylamine, ethylenediamine, lysine, arginine, glucosamine, N-methylglucosamine, trihydroxy-methylethylamine, d;ethanolam;ne, d;ethylamine, p;perazine or procaine.
The formulat;ons are prepared ;n a manner known per se~ for example by m;x;ng, ;ncorporation by stirring~
d;ssolving etc. ~ith or in the pharmaceutical auxiliaries.
The amount present in a single dose can be, for example, bet~een about 50 and 1,500 mg of active compound, ~hile a daily dose can amount to about 0.5 to ~ 9, preferably 1 to 3 g.
-- ~L2~2~
E~ample 8.2 g of crystall;ne and anhydrous ceftaz;d;m (obta;ned by the method of Canadian Patent Application No. 452,043 are allol~ed to stand in air for t~o days. The relative atmospheric humidity was between 50 and 70% when the experiment was carried out. About 400 mg of water had been absorbed after the indicated period. A colorless crystall;ne ceftazidim contain;ng 1.5 mol of water is quantitatively produced, and this differs very characteristically from the anhydrous form and the pentahydrate of ceftazidim in the Debye-Scherrer diagram (cf. Table 1). Slight fluc-tuations in the ~ater content do not affect the struc-ture or qua~;ty of the crystals.
C22H22N67S2 x 1.5 H20 (573.62) C H N S H
calcu~ated: 46.07 4.39 14.65 11.18 4.70 found: 4~.1 4.3 14.6 11.7 4.4 The NMR spectrum in CF3COzD completely corres-ponds to that of the pentahydrate in respect of the C-H
proton shifts.
~2~3~:~7 Table 1 Character;st;c crystal d;ffract;on angles of ceftaz;d;m x 1 . 5 mo l H20 D;ffract;on angle d CA~ rel. int.
5 2~ (Cu-K~) ~7 6,75 13,1 10 8,80 10,4 100 11~7 7,56 10 13,0 6,80 25 14,25 6,21 15 16,25 , 5,45 20 16,60 5,34 25 18,50 4j79 25 13,90 4,69 20 19,40 4,57 55 20,80 4,27 ~.0 21,15 4,20 30 21,90 4,05 30 23,25 3,82 10 24,70 3,60 15 25,20 3,53 20 26,30 3,38 10 26,5-0 3,36 10 27,10 3,29 10 2S 28,25 3,16 10
German Offenlegungsschr;ft 3,037,102) has h;therto been the only crystall;ne form wh;ch ;s well su;ted for parenteral use.
It is known that the stab;l;ty of cephalosporins ;s l;mited and that they readily decompose on storage.
The cause of this ;s the h;gh sensitivity to hydrolysis of the ~-lactam ring ~h;ch can even react slowly w;th water bound in the crystal latt;cs when the molecule ;s exposed to heat stress or is sto'red for a prolonged per;od at room temperature. Thus ;t is very important to employ the most stable crystall;ne form poss;ble for med;cal use of a cephalosporin antibiotic.
It has now been found that ceftaz;d;m can be con-verted ;nto a new crystall;ne mod;f;cation which is dis-t;ngu;shed from the pentahydrate by ;ncreased stab;l;ty to heat and ;s part;cularly ~ell su;ted for a parenteral formulat;on.
Thus the ;nvent;on relates to a crystall;ne ceftaz;d;m x 1.5 mol water~ ;ts'pharmaceutical formula-t;ons, and a process for ;ts preparat;on wh;ch compr;ses rehydrat;ng anhydrous crystalline ceftazid;m in mo;st ~24~t297 a;r until the indicated amount of water has been absorbed.
The crystall;ne mod;f;cation accord;ng to the invention has a characteristic Debye-Scherrer diagram ~Table 1) wh;ch proves the presence of a new crystalline form having new phys;cal and chemicaL properties.
The water content of ~he ceftazidim crystall;ne mod;fication according to the invention can vary by 0.2 to 0.4 mol, depend;ng on the atmospheric humidity under which the samples are manipulated and investigated, without any change in the crystalline modification bein observed.
The anhydrous crystalline form ~hich can be employed as start;ng mater;al can be obtained as cla;med 5 in Canadian Patent Application No. 452,043 by dehydrat;on of a crystall;ne ceftazidim hydrate, preferably the pentahydrate, to constant ~e;ght~
The absorption of water can be carried out using a;r under normal amb;en~ condit;ons or hav;ng an increased moisture content, such as, for example, 50 to 80Z relative atmospher;c humidity. The mo;sture content of the a;r can also be art;fic;ally increased in a known manner, for example by prev;ously mix;ng with ~ater vapor.
The desired amount of water in the crystals is followed by weight checks and, after achieving complete conversion of the crystals into a hydrate containing 1.5 mol of water, absorption is terminated.
As a rule, rehydration is carried out at room ~ , , `
L3;;~9~
~, temperature, bu~ it can also take place at elevated tfor example 40C) or reduced temperatures tfor example 1 0 C ) The time for the rehydration depends, in par-S ticular, on the particle size of the starting material, the thickness of the layer of material and the external conditions, such as, for example, the atmospheric humi-dity and the temperature. Thus, for example, it can be bet~een several hours and days.
The crystalline mod;fication according to the invention exhibits a higher stability than ceftazidim pentahydrate on storage of the samples under heat stress, and is thus ~ore suited for medical use.
The compound accord;ng to the invention is a valuable antibiotic ~hich is suited for controlling Gram-positive and, in particular, 6ram-negative ;nfections (cf. German Offenlegungsschrift 2,921,316).
Thus, the invention also relates to pharmaceuti-cal formulations ~hich contain the compound according to the invention, such as, for examp~e, solutions, suspen-sions or emulsions in oily or aqueous vehicles.
The compound according to the invention can be used as such or combined ~ith auxiliaries customarily employed in therapy, such as, for example, formulating agents, solvents, suspending agents and/or dispersants.
It ;s also possible for the active compound, before being used, to be present in the formulation in the form of a powder, for example, for dissoLution in, for ex-ample, sterile and pyrogen-free ~ater. In order to ,`
prepare aqueous solutions, the act;ve compound is advan-tageously dissolved by the addition of a basic aux;liary, such as, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium car-bonate, calcium carbonate, magnesiurn carbonate, tri-hydroxymethylmethylamine, ethylenediamine, lysine, arginine, glucosamine, N-methylglucosamine, trihydroxy-methylethylamine, d;ethanolam;ne, d;ethylamine, p;perazine or procaine.
The formulat;ons are prepared ;n a manner known per se~ for example by m;x;ng, ;ncorporation by stirring~
d;ssolving etc. ~ith or in the pharmaceutical auxiliaries.
The amount present in a single dose can be, for example, bet~een about 50 and 1,500 mg of active compound, ~hile a daily dose can amount to about 0.5 to ~ 9, preferably 1 to 3 g.
-- ~L2~2~
E~ample 8.2 g of crystall;ne and anhydrous ceftaz;d;m (obta;ned by the method of Canadian Patent Application No. 452,043 are allol~ed to stand in air for t~o days. The relative atmospheric humidity was between 50 and 70% when the experiment was carried out. About 400 mg of water had been absorbed after the indicated period. A colorless crystall;ne ceftazidim contain;ng 1.5 mol of water is quantitatively produced, and this differs very characteristically from the anhydrous form and the pentahydrate of ceftazidim in the Debye-Scherrer diagram (cf. Table 1). Slight fluc-tuations in the ~ater content do not affect the struc-ture or qua~;ty of the crystals.
C22H22N67S2 x 1.5 H20 (573.62) C H N S H
calcu~ated: 46.07 4.39 14.65 11.18 4.70 found: 4~.1 4.3 14.6 11.7 4.4 The NMR spectrum in CF3COzD completely corres-ponds to that of the pentahydrate in respect of the C-H
proton shifts.
~2~3~:~7 Table 1 Character;st;c crystal d;ffract;on angles of ceftaz;d;m x 1 . 5 mo l H20 D;ffract;on angle d CA~ rel. int.
5 2~ (Cu-K~) ~7 6,75 13,1 10 8,80 10,4 100 11~7 7,56 10 13,0 6,80 25 14,25 6,21 15 16,25 , 5,45 20 16,60 5,34 25 18,50 4j79 25 13,90 4,69 20 19,40 4,57 55 20,80 4,27 ~.0 21,15 4,20 30 21,90 4,05 30 23,25 3,82 10 24,70 3,60 15 25,20 3,53 20 26,30 3,38 10 26,5-0 3,36 10 27,10 3,29 10 2S 28,25 3,16 10
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of crystalline (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oximino)acetamido]-3-(1-pyridinimmethyl)-3-cephem-4-carboxylate x 1.5 mol water, which comprises rehydrating anhydrous crystalline (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oximino)acetamido]-3-(1-pyridi-niummethyl)-3-cephem-4-carboxylate in moist air until the indicated amount of water has been absorbed.
2. Crystalline (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oximino)acetamido]-3-(1-pyridinium-methyl)-3-cephem-4-carboxylate-x 1.5 mol water.
3. Pharmaceutical formulations active against bac-terial infections, which contain crystalline (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oximino)-acetamido]-3-(1-pyridiniummethyl)-3-cephem-4-carboxylate x 1.5 mol water, in admixture with one or more pharmaceutically acceptable auxiliaries, formulating agents, solvents, suspending agents or dispersants.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3313816.8 | 1983-04-16 | ||
| DE19833313816 DE3313816A1 (en) | 1983-04-16 | 1983-04-16 | NEW CEFTAZIDIM CRYSTAL MODIFICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1243297A true CA1243297A (en) | 1988-10-18 |
Family
ID=6196559
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000452042A Expired CA1243297A (en) | 1983-04-16 | 1984-04-13 | Crystalline modification of ceftazidim |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0122584A3 (en) |
| JP (1) | JPS59199689A (en) |
| KR (1) | KR910004300B1 (en) |
| AU (1) | AU571507B2 (en) |
| CA (1) | CA1243297A (en) |
| DE (1) | DE3313816A1 (en) |
| DK (1) | DK120084A (en) |
| ES (1) | ES8501768A1 (en) |
| GR (2) | GR81980B (en) |
| PT (1) | PT78419B (en) |
| ZA (1) | ZA842775B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3313818A1 (en) * | 1983-04-16 | 1984-10-18 | Hoechst Ag, 6230 Frankfurt | NEW CEFTAZIDIM CRYSTAL MODIFICATION |
| DE3313816A1 (en) * | 1983-04-16 | 1984-10-18 | Hoechst Ag, 6230 Frankfurt | NEW CEFTAZIDIM CRYSTAL MODIFICATION |
| US4537959A (en) * | 1984-03-26 | 1985-08-27 | Eli Lilly And Company | Crystalline cephalosporin antibiotic salt |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4054738A (en) * | 1975-12-22 | 1977-10-18 | Eli Lilly And Company | Sodium cefamandole crystalline forms |
| AR229883A1 (en) * | 1978-05-26 | 1983-12-30 | Glaxo Group Ltd | PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC (6R, 7R) -7 - ((Z) -2- (2-AMINOTIAZOL-4-IL) -2- (2-CARBOXIPROP-2-OXIIMINO) -ACETAMIDO) -3- (1 -PIRIDINOMETIL) -CEF-3-EM-4-CARBOXYLATE |
| FR2466469A1 (en) * | 1979-10-02 | 1981-04-10 | Glaxo Group Ltd | CEPHALOSPORINE BISCHLORHYDRATE, PROCESS FOR PREPARING THE SAME AND USES THEREOF, IN PARTICULAR THERAPEUTICS |
| US4329453A (en) * | 1979-10-02 | 1982-05-11 | Glaxo Group Limited | Cephalosporin antibiotic |
| DE3313816A1 (en) * | 1983-04-16 | 1984-10-18 | Hoechst Ag, 6230 Frankfurt | NEW CEFTAZIDIM CRYSTAL MODIFICATION |
-
1983
- 1983-04-16 DE DE19833313816 patent/DE3313816A1/en not_active Withdrawn
-
1984
- 1984-02-28 DK DK120084A patent/DK120084A/en not_active Application Discontinuation
- 1984-04-10 EP EP84103976A patent/EP0122584A3/en not_active Withdrawn
- 1984-04-13 ES ES531583A patent/ES8501768A1/en not_active Expired
- 1984-04-13 ZA ZA842775A patent/ZA842775B/en unknown
- 1984-04-13 PT PT78419A patent/PT78419B/en not_active IP Right Cessation
- 1984-04-13 GR GR74413A patent/GR81980B/el unknown
- 1984-04-13 CA CA000452042A patent/CA1243297A/en not_active Expired
- 1984-04-13 GR GR74414A patent/GR81981B/el unknown
- 1984-04-14 KR KR1019840001985A patent/KR910004300B1/en not_active IP Right Cessation
- 1984-04-16 AU AU26858/84A patent/AU571507B2/en not_active Ceased
- 1984-04-16 JP JP59076422A patent/JPS59199689A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP0122584A2 (en) | 1984-10-24 |
| GR81980B (en) | 1984-12-12 |
| DK120084A (en) | 1984-10-17 |
| ZA842775B (en) | 1984-11-28 |
| PT78419A (en) | 1984-05-01 |
| GR81981B (en) | 1984-12-12 |
| DK120084D0 (en) | 1984-02-28 |
| AU2685884A (en) | 1984-10-18 |
| AU571507B2 (en) | 1988-04-21 |
| ES531583A0 (en) | 1984-12-01 |
| EP0122584A3 (en) | 1985-08-28 |
| PT78419B (en) | 1986-06-02 |
| ES8501768A1 (en) | 1984-12-01 |
| DE3313816A1 (en) | 1984-10-18 |
| KR840008371A (en) | 1984-12-14 |
| JPS59199689A (en) | 1984-11-12 |
| KR910004300B1 (en) | 1991-06-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |