Note: Descriptions are shown in the official language in which they were submitted.
~z43z9~7
-- 2
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
-- 3 --
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
~ , ,
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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
,`
3297
- 5 -
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~
- 6 -
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
-- 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
