Process for formulation of antibiotic compounds

Details Process for formulation of antibiotic compounds Process for formulation of antibiotic compounds

2001-04-27

2002-11-26

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S350000

Reexamination Certificate

active

06486150

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for preparing a stabilized form of antibiotic compounds, in particular a carbapenem antibiotic composition.
BACKGROUND OF THE INVENTION
Betalactams, a broader class of antibiotics which is further defined as carbapenems are useful for the treatment of infectious diseases including gram positive and negative, and aerobic and anaerobic bacteria. Carbapenems were first isolated from fermentation media in 1974 and were found to have broad-spectrum antibacterial activity. Since this discovery substantial investigations have been made into new carbapenem derivatives and many hundreds of patents and scientific papers have been published. The commercially marketed carbapenem is imipenem (N-formimidoyl thienamycin), which has a broad range of antibacterial activity. This compound can be used in the treatment of any disease that is conventionally treated with antibiotics, for example in the treatment of bacterial infection in mammals including humans.
It has been reported that dimerization of carbapenem is inhibited via the formation of a reversible equilibrium adduct between carbon dioxide and monosodium salt of carbapenem compound as shown below, where K
a
and K
eq
are equilibrium constants of the reactions.
During the manufacture of bulk antibiotic products such as carbapenem antibiotic, the pharmaceutical compound is prepared by chemical synthesis from raw materials in large quantities. Carbapenem antibiotic compounds are prepared in large batches as salt form, monosodium salt as shown above, which are weak crystalline solids, hygroscopic at ambient conditions, and unstable at room and refrigerated temperatures. Because the compound is unstable at a temperature above about −20° C., the bulk compounds must be stored at a low temperature (about −20° C.) to prevent degradation into dimers or open ring by-products. Although the unstable compound of carbapenem, after bulk manufacturing, can be stored for long periods of time at a low temperature, it must be converted into a stable formulation prior to use as once-a-day antimicrobial agent for intravenous (IV) or intramuscular (IM) administration.
Several reported cases for preparing carbapenem antibiotic compounds have shortcomings of teaching how to achieve a stable form of carbapenem antibiotics in its final formulation and manufacturing process. In particular, they fail to teach how to achieve the conversion of salt-containing carbapenem compound to a formulation exhibiting acceptable levels of degradates required for solid state and reconstitution stability for dosing to patients.
For example, Almarsson et al. (WO 98/18800) discloses a method for stabilizing carbapenem antibiotics by carboxylating the pyrrolidinyl amino acid with a carbon dioxide source, but fails to teach the steps necessary to obtain the stable form of carbapenem during its formulation process.
Zimmerman et al. (U.S. Pat. No. 5,952,323) relates a method of stabilizing a carbapenem compound by incorporating carbon dioxide source, but it also does not provide how to achieve the stabilized form of carbon dioxide adduct in its final composition.
In light of the above, an objective of the present invention is to provide a process for formulating a final product of stable antibiotic compound, in particular carbapenem antibiotic for the treatment of infectious diseases which include gram positive and negative, and aerobic and anaerobic bacteria. Another object of the present invention is to provide a novel manufacturing process to prepare the final formulation product of carbapenem antibiotic with acceptable levels of degradates, solid state stability and solution stability for dosing.
SUMMARY OF THE INVENTION
The present invention is directed to a process for preparing a final formulation product of a compound of Formula I,
or its pharmaceutically acceptable salt, hydrate or solvate wherein,
R
1
is:
(a) 1-hydroxyethyl,
(b) 1-fluoroethyl, or
(c) hydroxymethyl;
R
2
and R
3
are independently:
(a) hydrogen, or
(b) (C
1
-C
6
)-alkyl;
R
4
, R
5
and R
6
are independently
(a) hydrogen
(b) (C
1
-C
6
)-alkyl, or
(c) alkali-metal or alkali earth-metal wherein the alkali-metal or alkali earth-metal is sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium; and
R
7
and R
8
are independently:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) (C
1
-C
6
)-alkyl,
(e) nitro,
(f) hydroxy,
(g) carboxy,
(h) (C
1
-C
6
)-alkoxy,
(i) (C
1
-C
6
)-alkoxycarbonyl,
(j) aminosulphonyl,
(k) (C
1
-C
6
)-alkylaminosulphonyl,
(l) di-(C
1
-C
6
)-alkylaminosulphonyl,
(m) carbamoyl,
(n) (C
1
-C
6
)-alkylcarbamoyl,
(o) di-(C
1
-C
6
)-alkylcarbamoyl,
(p) trifluoromethyl,
(q) sulphonic acid,
(r) amino,
(s) (C
1
-C
6
)-alkylamino,
(t) di-(C
1
-C
6
)-alkylmino,
(u) (C
1
-C
6
)-alkanoylamino,
(v) (C
1
-C
6
)-alkanoyl(N-(C
1
-C
6
)-alkyl)amino,
(w) (C
1
-C
6
)-alkanesulphonamido, or
(x) (C
1
-C
6
)-alkyl-S(O)
n
wherein n is 0-2;
comprising the steps of:
(1) charging a solution of carbon dioxide source having a pH range of about 6.0 to about 12.0 into a reaction vessel;
(2) adding an effective amount of a mole ratio of a base and an active ingredient into the reaction vessel containing the solution of carbon dioxide source to maintain pH at about 6.0 to about 9.0 and a temperature range of about −3° C. to about 15° C.;
(3) lyophilizing the solution of Step (2) to yield the final formulation product of a compound of formula I with less than about 10% of moisture content.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing a stable form of carbapenem compound in its formulation and manufacturing processes. More specifically, the present invention involves a process for preparing a stabilized carbon dioxide adduct of carbapenem antibiotic by incorporating suitable carbon dioxide source to unstable salt form of carbapenem antibiotic, in particular monosodium salt of carbapenem, at suitable reaction conditions. The stable carbon dioxide adduct of the carbapenem antibiotic formulation is useful for the treatment of bacterial infections in mammal patients, which can be administered intravenously or intramuscularly.
The present invention is directed to a process for preparing a final formulation product of a compound of Formula I,
or its pharmaceutically acceptable salt, hydrate or solvate wherein,
R
1
is:
(a) 1-hydroxyethyl,
(b) 1-fluoroethyl, or
(c) hydroxymethyl;
R
2
and R
3
are independently:
(a) hydrogen, or
(b) (C
1
-C
6
)-alkyl;
R
4
, R
5
, and R
6
are independently
(a) hydrogen
(b) (C
1
-C
6
)-alkyl, or
(c) alkali-metal or alkali earth-metal wherein the alkali-metal or alkali earth-metal is sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium; and
R
7
and R
8
are independently:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) (C
1
-C
6
)-alkyl,
(e) nitro,
(f) hydroxy,
(g) carboxy,
(h) (C
1
-C
6
)-alkoxy,
(i) (C
1
-C
6
)-alkoxycarbonyl,
(j) aminosulphonyl,
(k) (C
1
-C
6
)-alkylaminosulphonyl,
(l) di-(C
1
-C
6
)-alkylaminosulphonyl,
(m) carbamoyl,
(n) (C
1
-C
6
)-alkylcarbamoyl,
(o) di-(C
1
-C
6
)-alkylcarbamoyl,
(p) trifluoromethyl,
(q) sulphonic acid,
(r) amino,
(s) (C
1
-C
6
)-alkylamino,
(t) di-(C
1
-C
6
)-alkylmino,
(u) (C
1
-C
6
)-alkanoylamino,
(v) (C
1
-C
6
)-alkanoyl(N-(C
1
-C
6
)-alkyl)amino,
(w) (C
1
-C
6
)-alkanesulphonamido, or
(x) (C
1
-C
6
)-alkyl-S(O)
n
wherein n is 0-2;
comprising the steps of:
(1) charging a solution of carbon dioxide source having a pH range of about 6.0 to about 12.0 into a reaction vessel;
(2) adding an effective amount of a mole ratio of a base and an active ingredient into the reaction vessel containing the solution of carbon dioxide source to maintain pH at about 6.0 to about 9.0 and a temperature range of about −3° C. to about 15° C.;
(3) lyophilizing the solution of Step (2) to yield the final formulation product of a compound of formula I with less than about 10% of moisture content.
A preferred embodiment of the present invention is a process for preparing a formulation of a compound of Formula Ia,

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