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US 6,486,150 B2Granted
Process for formulation of antibiotic compounds
AssigneeMerck & Co., Inc.
InventorsWilliam A. Hunke, Kathleen J. Illig, Anand Kanike, Scott D. Reynolds, Stelios C. Tsinontides, Anthony S. Al-Dehneh, Hiren S. Patel
Life of this patent
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Abstract
The present invention involves a process for preparing a stable final formulation product of a compound of formula I, or its pharmaceutically acceptable salt, hydrate or solvate by incorporating a suitable carbon dioxide source to an unstable monosodium adduct of carbapenem antibiotic compound.
Claims40
A process for preparing a final formulation product of a compound of formula I,
- or its pharmaceutically acceptable salt, or hydrate wherein,
- R1 is:
- (a) 1-hydroxyethyl,
- (b) 1-fluoroethyl, or
- (c) hydroxymethyl;
- R2 and R3 are independently:
- (a) hydrogen, or
- (b) (C1-C6)-alkyl;
- R4, R5, and R6 are independently
- (a) hydrogen
- (b) (C1-C6)-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
- R7 and R8 are independently:
- (a) hydrogen,
- (b) halo,
- (c) cyano,
- (d) (C1-C6)-alkyl,
- (e) nitro,
- (f) hydroxy,
- (g) carboxy,
- (h) (C1-C6)-alkoxy,
- (i) (C1-C6)-alkoxycarbonyl,
- (j) aminosulphonyl,
- (k) (C1-C6)-alkylaminosulphonyl,
- (l) di-(C1-C6)-alkylaminosulphonyl,
- (m) carbamoyl,
- (n) (C1-C6)-alkylcarbamoyl,
- (o) di-(C1-C6)-alkylcarbamoyl,
- (p) trifluoromethyl,
- (q) sulphonic acid,
- (r) amino,
- (s) (C1-C6)-alkylamino,
- (t) di-(C1-C6)-alkylmino,
- (u) (C1-C6)-alkanoylamino,
- (v) (C1-C6)-alkanoyl(N-(C1-C6)-alkyl)amino,
- (w) (C1-C6)-alkanesulphonamido, or
- (x) (C1-C6)-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.
39 more elements
A process for preparing a final formulation product of a compound of Formula Ia,
- or its pharmaceutically acceptable salt, or hydrates wherein,
- R4, R5, and R6 are independently:
- (a) hydrogen
- (b) (C1-C6)-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;
- 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 Ia with less than about 10% of moisture content.
6 more elements
Dependencies are inferred from the claim text.