Tazobactam Arginine Compositions
This disclosure provides compositions containing solid forms of tazobactam arginine, and methods of manufacturing and using these compositions.
1 . A pharmaceutical composition comprising a compound having a beta-lactam chemical sub-structure and crystalline tazobactam arginine polymorph Ia.
2 . The pharmaceutical composition of claim 1 , prepared by lyophilization.
3 . The pharmaceutical composition of claim 1 , obtained from an aqueous solution comprising L-arginine and tazobactam acid.
4 . The pharmaceutical composition of claim 3 , wherein the aqueous solution has a pH of about 5.9 to about 10.5 prior to lyophilization.
5 . The pharmaceutical composition of claim 1 , wherein the beta-lactam compound is (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.
6 . The pharmaceutical composition of claim 1 , wherein the beta-lactam compound is selected from the group consisting of the compounds in Table 2:
TABLE 2
No.
IUPAC Name
CAS No.
1
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-
61477-96-1
phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-
2-carboxylic acid
2
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-
61-33-6
zabicyclo[3.2.0]heptane-2-carboxylic acid
3
(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-
74431-23-5
7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4
(5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia-
106560-14-9
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid faropenem
5
(2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-
61-72-3
3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
6
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-
72558-82-8
yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-
bicyclo[4.2.0] oct-2-ene-2-carboxylate
7
(6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-
63527-52-6
(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
8
(6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-
400827-46-5
3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-
yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
9
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-
88040-23-7
3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-
bicyclo[4.2.0]oct-2-ene-2-carboxylate
10
(6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-
55268-75-2
(methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
11
(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-
73384-59-5
(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-
1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
12
(2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-
26787-78-0
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
13
3-[5-(dimethylcarbamoyl) pyrrolidin-2-yl] sulfanyl-6-(1-hydroxyethyl)-4-
119478-56-7
methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
7 . The pharmaceutical composition of claim 1 , further comprising a pharmaceutically acceptable carrier or diluent.
8 . The pharmaceutical composition of claim 1 , formulated for intravenous injection or infusion.
9 . The pharmaceutical composition of claim 1 , having a molar ratio of about 1:1 between tazobactam acid and arginine.
10 . A pharmaceutical composition obtained from a solution formed by dissolving a compound having a beta-lactam chemical sub-structure and crystalline tazobactam arginine polymorph Ia.
11 . The pharmaceutical composition of claim 10 , obtained by a process comprising lyophilizing the solution to obtain pharmaceutical composition.
12 . The pharmaceutical composition of claim 10 , wherein the solution comprises L-arginine and tazobactam acid.
13 . The pharmaceutical composition of claim 10 , wherein the beta-lactam compound is (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.
14 . The pharmaceutical composition of claim 11 , wherein the solution has a pH of about 5.9 to about 10.5 prior to lyophilization.
15 . The pharmaceutical composition of claim 10 , wherein the beta-lactam compound is selected from the group consisting of the compounds in Table 2:
TABLE 2
No.
IUPAC Name
CAS No.
1
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-
61477-96-1
phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-
2-carboxylic acid
2
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-
61-33-6
zabicyclo[3.2.0]heptane-2-carboxylic acid
3
(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-
74431-23-5
7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4
(5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia-
106560-14-9
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid faropenem
5
(2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-
61-72-3
3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
6
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-
72558-82-8
yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-
bicyclo[4.2.0] oct-2-ene-2-carboxylate
7
(6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-
63527-52-6
(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
8
(6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-
400827-46-5
3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-
yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
9
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-
88040-23-7
3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-
bicyclo[4.2.0]oct-2-ene-2-carboxylate
10
(6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-
55268-75-2
(methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
11
(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-
73384-59-5
(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-
1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
12
(2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-
26787-78-0
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
13
3-[5-(dimethylcarbamoyl) pyrrolidin-2-yl] sulfanyl-6-(1-hydroxyethyl)-4-
119478-56-7
methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
16 . A pharmaceutical composition obtained by combining a compound having a beta-lactam chemical sub-structure selected from compounds in Table 2 and a tazobactam composition obtained from a solution formed by dissolving a crystalline tazobactam arginine polymorph Ia:
TABLE 2
No.
IUPAC Name
CAS No.
1
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-
61477-96-1
phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-
2-carboxylic acid
2
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-
61-33-6
zabicyclo[3.2.0]heptane-2-carboxylic acid
3
(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-
74431-23-5
7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4
(5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia-
106560-14-9
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid faropenem
5
(2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-
61-72-3
3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
6
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-
72558-82-8
yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-
bicyclo[4.2.0] oct-2-ene-2-carboxylate
7
(6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-
63527-52-6
(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
8
(6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-
400827-46-5
3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-
yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
9
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-
88040-23-7
3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-
bicyclo[4.2.0]oct-2-ene-2-carboxylate
10
(6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-
55268-75-2
(methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
11
(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-
73384-59-5
(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-
1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
12
(2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-
26787-78-0
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
13
3-[5-(dimethylcarbamoyl) pyrrolidin-2-yl] sulfanyl-6-(1-hydroxyethyl)-4-
119478-56-7
methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
17 . The pharmaceutical composition of claim 16 , wherein the solution is an aqueous solution, and the tazobactam composition is obtained by a process comprising lyophilizing an aqueous solution comprising the crystalline tazobactam arginine polymorph Ia to obtain a lyophilized tazobactam composition, and combining the tazobactam composition.
18 . The pharmaceutical composition of claim 16 , wherein the solution comprises L-arginine and tazobactam acid.
19 . The pharmaceutical composition of claim 16 , wherein the beta-lactam compound is (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.
20 . The pharmaceutical composition of claim 17 , wherein the solution has a pH of about 5.9 to about 10.5 prior to lyophilization.
21 . A pharmaceutical composition comprising a tazobactam composition obtained from a solution formed by dissolving a tazobactam acid in an aqueous solution and lyophilizing the solution to obtain the tazobactam composition.
22 . The pharmaceutical composition of claim 21 , obtained by a process further comprising the step of combining a compound having a beta-lactam chemical sub-structure selected from compounds in Table 2 with the tazobactam composition:
TABLE 2
No.
IUPAC Name
CAS No.
1
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-
61477-96-1
phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-
2-carboxylic acid
2
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-
61-33-6
zabicyclo[3.2.0]heptane-2-carboxylic acid
3
(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-
74431-23-5
7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4
(5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia-
106560-14-9
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid faropenem
5
(2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-
61-72-3
3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
6
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-
72558-82-8
yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-
bicyclo[4.2.0] oct-2-ene-2-carboxylate
7
(6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-
63527-52-6
(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
8
(6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-
400827-46-5
3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-
yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
9
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-
88040-23-7
3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-
bicyclo[4.2.0]oct-2-ene-2-carboxylate
10
(6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-
55268-75-2
(methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
11
(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-
73384-59-5
(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-
1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
12
(2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-
26787-78-0
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
13
3-[5-(dimethylcarbamoyl) pyrrolidin-2-yl] sulfanyl-6-(1-hydroxyethyl)-4-
119478-56-7
methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
23 . The pharmaceutical composition of claim 21 , wherein the solution further comprises L-arginine.
24 . The pharmaceutical composition of claim 21 , wherein the solution has a pH of about 5.9 to about 10.5 prior to lyophilization.
25 . The pharmaceutical composition of claim 22 , wherein the beta-lactam compound is (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.