U.S. patent application number 14/541890 was filed with the patent office on 2015-03-12 for tazobactam arginine compositions.
This patent application is currently assigned to Calixa Therapeutics, Inc.. The applicant listed for this patent is Calixa Therapeutics, Inc.. Invention is credited to Nicole Miller Damour, Jian-Qiao Gu, Valdas Jurkauskas, Jan-Ji Lai, Pradip M. Pathare, Joseph Terracciano.
Application Number | 20150072957 14/541890 |
Document ID | / |
Family ID | 48671186 |
Filed Date | 2015-03-12 |
United States Patent
Application |
20150072957 |
Kind Code |
A1 |
Lai; Jan-Ji ; et
al. |
March 12, 2015 |
Tazobactam Arginine Compositions
Abstract
This disclosure provides compositions containing solid forms of
tazobactam arginine, and methods of manufacturing and using these
compositions.
Inventors: |
Lai; Jan-Ji; (Westborough,
MA) ; Gu; Jian-Qiao; (Lexington, MA) ;
Pathare; Pradip M.; (Lexington, MA) ; Jurkauskas;
Valdas; (Cambridge, MA) ; Terracciano; Joseph;
(Concord, MA) ; Damour; Nicole Miller; (Belmont,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Calixa Therapeutics, Inc. |
Lexington |
MA |
US |
|
|
Assignee: |
Calixa Therapeutics, Inc.
Lexington
MA
|
Family ID: |
48671186 |
Appl. No.: |
14/541890 |
Filed: |
November 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14181041 |
Feb 14, 2014 |
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14541890 |
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13828534 |
Mar 14, 2013 |
8685957 |
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14181041 |
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13628742 |
Sep 27, 2012 |
8476425 |
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13828534 |
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Current U.S.
Class: |
514/80 ; 514/192;
514/196; 514/197 |
Current CPC
Class: |
A61K 31/431 20130101;
A61K 31/675 20130101; C07D 499/897 20130101; A61K 31/496 20130101;
A61K 31/53 20130101; Y02A 50/473 20180101; C07D 499/14 20130101;
A61K 31/4353 20130101; A61K 31/403 20130101; C07D 499/86 20130101;
A61K 31/43 20130101; A61K 31/546 20130101; A61K 31/4188 20130101;
A61K 31/444 20130101; A61K 9/19 20130101 |
Class at
Publication: |
514/80 ; 514/192;
514/196; 514/197 |
International
Class: |
C07D 499/887 20060101
C07D499/887; A61K 31/496 20060101 A61K031/496; A61K 9/19 20060101
A61K009/19; A61K 31/546 20060101 A61K031/546; A61K 31/675 20060101
A61K031/675; A61K 31/431 20060101 A61K031/431; A61K 31/43 20060101
A61K031/43 |
Claims
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-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c 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-US-00004 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-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c 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-US-00005 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-US-00006 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-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c 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-US-00007 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-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c acid.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/181,041, filed on Feb. 14, 2014, which was
a continuation of U.S. patent application Ser. No. 13/828,534,
filed on Mar. 14, 2013, which was a continuation of U.S. patent
application Ser. No. 13/628,742, filed on Sep. 27, 2012. The entire
contents of these applications are incorporated herein by
reference.
TECHNICAL FIELD
[0002] This disclosure relates to solid forms of
(2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azab-
icyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (tazobactam),
and related compositions and methods.
BACKGROUND
[0003] The crystal state of a compound may be important when the
compound is used for pharmaceutical purposes. Compared with an
amorphous solid, the solid physical properties of a crystalline
compound may change, which may affect its suitability for
pharmaceutical use. For example, a particular crystalline compound
may overcome the disadvantage of other solid forms of the compound
that readily absorb moisture (e.g., high hygroscopicity). For an
ionic drug substance, high hygroscopicity may diminish the drug
product's stability profile by a host of mechanisms, as the drug
substance may have a propensity to absorb water. Water that is
absorbed from the environment (packaging materials, exposure to
air, or in the case of formulated products, from other materials),
may lead to degradation products and/or impurities in a drug
product or add to the cost of manufacturing the drug product with
acceptably low levels of water.
[0004] One compound that can be obtained in amorphous or various
crystalline salt forms is
(2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azab-
icyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide, or tazobactam.
There is a need for solid forms of tazobactam with reduced
hygroscopicity for use in drug substance and drug product
development.
SUMMARY
[0005] Solid forms of tazobactam (e.g., arginine salt forms of
tazobactam) and compositions comprising these solid forms, are
provided herein, in addition to various methods of preparing these
compositions. Compared with previous crystalline forms of
tazobactam, certain crystalline tazobactam arginine solid forms are
provided herein that have the advantageous characteristic of being
less hygroscopic. These crystalline tazobactam arginine solid forms
can have good thermal stability and light stability in the process
of preparation, packing, transportation and storage. Crystalline
compounds of tazobactam arginine can also possess other properties
that may be beneficial to the preparation of various drug
formulations.
[0006] Crystalline tazobactam arginine, and hydrates and solvates
thereof, can be obtained in various solid forms. Tazobactam
arginine can be a salt consisting of the conjugate base of
(2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azab-
icyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (tazobactam) and
the conjugate acid of (S)-2-amino-5-guanidinopentanoic acid
(L-arginine) in a 1:1 ratio, as represented by the structure
below.
##STR00001##
[0007] In one aspect, provided herein is a particularly preferred
crystalline tazobactam arginine solid form (designated herein as
"polymorph Ia" or "tazobactam arginine polymorph Ia"),
characterized by an X-ray powder diffraction pattern having peaks
expressed in degrees 2-Theta at angles of
4.8.degree..+-.0.3.degree., 8.9.degree..+-.0.3.degree.,
11.3.degree..+-.0.3.degree., 14.9.degree..+-.0.3.degree.,
18.0.degree..+-.0.3.degree., 19.4.degree..+-.0.3.degree.,
21.3.degree..+-.0.3.degree., 22.8.degree..+-.0.3.degree., and
24.3.degree..+-.0.3.degree.. The crystalline tazobactam arginine
can be further characterized by a differential scanning calorimetry
thermogram having a characteristic peak expressed in units of
.degree. C. at a temperature of 209.2.+-.3. In another embodiment,
the crystalline tazobactam arginine is further characterized by a
thermogravimetry curve with an onset temperature of 201.9.degree.
C..+-.3.degree. C.
[0008] Also provided are pharmaceutical compositions comprising a
compound having a beta-lactam chemical sub-structure (e.g., a
beta-lactam antibiotic compound) and crystalline tazobactam
arginine (e.g., of the polymorph Ia solid form).
[0009] In another aspect, provided herein is a method for the
treatment of bacterial infections in a mammal, comprising
administering to said mammal a therapeutically effective amount of
a crystalline tazobactam arginine compound (e.g., of the polymorph
Ia solid form). The crystalline tazobactam arginine can be
characterized by an X-ray powder diffraction pattern having peaks
expressed in degrees 2-Theta at angles of
4.8.degree..+-.0.3.degree., 8.9.degree..+-.0.3.degree.,
11.3.degree..+-.0.3.degree., 14.9.degree..+-.0.3.degree.,
18.0.degree..+-.0.3.degree., 19.4.degree..+-.0.3.degree.,
21.3.degree..+-.0.3.degree., 22.8.degree..+-.0.3.degree. and
24.3.degree..+-.0.3.degree..
[0010] In another aspect, provided herein is a method for the
treatment of bacterial infections in a mammal, comprising
administering to said mammal a therapeutically effective amount of
a pharmaceutical composition comprising an beta-lactam compound and
a crystalline tazobactam arginine compound (e.g., of the polymorph
Ia solid form). The crystalline tazobactam arginine can be
characterized by an X-ray powder diffraction pattern having peaks
expressed in degrees 2-Theta at angles of
4.8.degree..+-.0.3.degree., 8.9.degree..+-.0.3.degree.,
11.3.degree..+-.0.3.degree., 14.9.degree..+-.0.3.degree.,
18.0.degree..+-.0.3.degree., 19.4.degree..+-.0.3.degree.,
21.3.degree..+-.0.3.degree., 22.8.degree..+-.0.3.degree. and
24.3.degree..+-.0.3.degree..
[0011] In another aspect, provided herein is a method for detecting
or identifying an agent that inhibits one or more
beta-lactamase-producing organisms, said method comprising
combining:
[0012] (a) a test agent;
[0013] (b) a composition comprising one or more
beta-lactamase-producing organisms; and
[0014] (c) crystalline tazobactam arginine, wherein the crystalline
tazobactam arginine is characterized by an X-ray powder diffraction
pattern having peaks expressed in degrees 2-Theta at angles of
4.8.degree..+-.0.3.degree., 8.9.degree..+-.0.3.degree.,
11.3.degree..+-.0.3.degree., 14.9.degree..+-.0.3.degree.,
18.0.degree..+-.0.3.degree., 19.4.degree..+-.0.3.degree.,
21.3.degree..+-.0.3.degree., 22.8.degree..+-.0.3.degree. and
24.3.degree..+-.0.3.degree.; and detecting or measuring a change in
the activity of the beta-lactamase-producing organisms, wherein a
decrease in the activity of the beta-lactamase-producing organisms
indicates that the test agent inhibits the beta-lactamase-producing
organisms.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 depicts the X-ray powder diffraction pattern of
polymorph Ia (Example 2).
[0016] FIG. 2 depicts the differential scanning calorimetry (DVS)
thermogram of polymorph Ia.
[0017] FIG. 3 depicts the thermogravimetry curve of polymorph
Ia.
[0018] FIG. 4 depicts the X-ray powder diffraction pattern of
polymorph Ib.
[0019] FIG. 5 depicts the X-ray powder diffraction pattern of
tazobactam arginine amorphous.
[0020] FIG. 6 depicts the X-ray power diffraction pattern of
polymorph Ia (Example 4).
[0021] FIG. 7 depicts the .sup.1H-NMR spectrum of polymorph Ia.
[0022] FIG. 8 depicts the DVS graph of tazobactam arginine
amorphous (Example 6a).
[0023] FIG. 9 depicts the DVS graph of polymorph Ia (Example
6b).
[0024] FIG. 10 depicts the DVS graph of amorphous tazobactam sodium
(Example 6c).
DETAILED DESCRIPTION
[0025] Tazobactam arginine may occur in an amorphous solid form or
in a crystalline solid form. Crystalline solid forms of tazobactam
arginine may exist in one or more unique polymorph forms, which may
additionally comprise one or more equivalents of water or solvent
(i.e., hydrates or solvates, respectively).
[0026] Tazobactam arginine is the salt of the conjugate base of
tazobactam and the conjugate acid of
(S)-2-amino-5-guanidinopentanoic acid (L-arginine) in a 1:1 ratio,
as represented by the structure below.
##STR00002##
[0027] Accordingly, provided herein is crystalline tazobactam
arginine, and hydrates and solvates thereof. In particular,
provided herein is crystalline tazobactam arginine polymorph Ia,
also referred to herein as "polymorph Ia" or "tazobactam arginine
polymorph Ia", and crystalline tazobactam arginine polymorph Ib,
also referred to herein as "polymorph Ib" or "tazobactam arginine
polymorph Ib".
Polymorphism
[0028] The ability of a substance to exist in more than one crystal
form is defined as polymorphism; the different crystal forms of a
particular substance are referred to as "polymorphs." In general,
polymorphism is affected by the ability of a molecule of a
substance to change its conformation or to form different
intermolecular or intra-molecular interactions, particularly
hydrogen bonds, which is reflected in different atom arrangements
in the crystal lattices of different polymorphs. In contrast, the
overall external form of a substance is known as "morphology,"
which refers to the external shape of the crystal and the planes
present, without reference to the internal structure. Crystals can
display different morphology based on different conditions, such
as, for example, growth rate, stirring, and the presence of
impurities.
[0029] The different polymorphs of a substance can possess
different energies of the crystal lattice and, thus, in solid state
they can show different physical properties such as form, density,
melting point, color, stability, solubility, dissolution rate,
etc., which can, in turn, affect the stability, dissolution rate
and/or bioavailability of a given polymorph and its suitability for
use as a pharmaceutical and in pharmaceutical compositions.
[0030] Access to different polymorphs of tazobactam arginine is
desirable for other reasons as well. One such reason is that
different polymorphs of a compound (e.g., tazobactam arginine) can
incorporate different impurities, or chemical residues, upon
crystallization. Certain polymorphs incorporate very little, or no,
chemical residues. Accordingly, the formation of certain polymorph
forms of a compound may result in purification of the compound.
[0031] Tazobactam arginine polymorph Ia exhibits low hygroscopicity
relative to amorphous tazobactam arginine and amorphous tazobactam
sodium. Low hygroscopicity of a solid compound is desirable for
several reasons. For example, compounds that are highly hygroscopic
may be chemically unstable, or unsuitable for formulating as a drug
product due to changes of the drug form's physical characteristics
(e.g., bulk density, dissolution rate, etc.) that can occur if it
is stored in settings with varying relative humidity. Also,
hygroscopicity can impact large-scale manufacturing and handling of
a compound. For example, it may be difficult to determine the true
weight of a hygroscopic active agent when preparing a
pharmaceutical composition comprising that agent.
Characterization of Polymorphs
[0032] In certain embodiments, the compounds of the invention are
identifiable on the basis of characteristic peaks in an X-ray
powder diffraction analysis. X-ray powder diffraction, also
referred to as XRPD, is a scientific technique using X-ray,
neutron, or electron diffraction on powder, microcrystalline, or
other solid materials for structural characterization of the
materials.
[0033] One embodiment of crystalline tazobactam arginine is
referred to as polymorph Ia (also referred to herein as "tazobactam
arginine polymorph Ia") and is characterized by an X-ray powder
diffraction pattern having one or more characteristic peaks
expressed in degrees 2-Theta at angles selected from
8.9.degree..+-.0.3.degree., 18.0.degree..+-.0.3.degree. and
21.3.degree..+-.0.3.degree.. In another embodiment, polymorph Ia is
characterized by an X-ray powder diffraction pattern having one or
more peaks expressed in degrees 2-Theta at angles selected from
4.8.degree..+-.0.3.degree., 11.3.degree..+-.0.3.degree. and
14.9.degree..+-.0.3.degree.. In still another embodiment, polymorph
Ia is characterized by an X-ray powder diffraction pattern having
one or more peaks expressed in degrees 2-Theta at angles selected
from 19.4.degree..+-.0.3.degree., 22.8.degree..+-.0.3.degree. and
24.3.degree..+-.0.3.degree..
[0034] In another embodiment, polymorph Ia is characterized by an
X-ray powder diffraction pattern having 3-6 peaks expressed in
degrees 2-Theta at angles selected from 8.9.degree..+-.0.3.degree.,
18.0.degree..+-.0.3.degree., 21.3.degree..+-.0.3.degree.,
4.8.degree..+-.0.3.degree., 11.3.degree..+-.0.3.degree.,
14.9.degree..+-.0.3.degree., 19.4.degree..+-.0.3.degree.,
22.8.degree..+-.0.3.degree. and 24.3.degree..+-.0.3.degree.. In a
particular embodiment, polymorph Ia is characterized by an X-ray
powder diffraction pattern having characteristic peaks expressed in
degrees 2-Theta at angles of 8.9.degree..+-.0.3.degree.,
18.0.degree..+-.0.3.degree. and 21.3.degree..+-.0.3.degree..
[0035] In yet another embodiment, polymorph Ia is characterized by
an X-ray powder diffraction pattern having 3-6 peaks expressed in
degrees 2-Theta at angles selected from 8.9.degree..+-.0.2.degree.,
18.0.degree..+-.0.2.degree., 21.3.degree..+-.0.2.degree.,
4.8.degree..+-.0.2.degree., 11.3.degree..+-.0.2.degree.,
14.9.degree..+-.0.2.degree., 19.4.degree..+-.0.2.degree.,
22.8.degree..+-.0.2.degree. and 24.3.degree..+-.0.2.degree.. In a
particular embodiment, polymorph Ia is characterized by an X-ray
powder diffraction pattern having characteristic peaks expressed in
degrees 2-Theta at angles of 8.9.degree..+-.0.2.degree.,
18.0.degree..+-.0.2.degree. and 21.3.degree..+-.0.2.degree..
[0036] In still another embodiment, polymorph Ia is characterized
by an X-ray powder diffraction pattern having 6-9 peaks expressed
in degrees 2-Theta at angles selected from
8.9.degree..+-.0.3.degree., 18.0.degree..+-.0.3.degree.,
21.3.degree..+-.0.3.degree., 4.8.degree..+-.0.3.degree.,
11.3.degree..+-.0.3.degree., 14.9.degree..+-.0.3.degree.,
19.4.degree..+-.0.3.degree., 22.8.degree..+-.0.3.degree. and
24.3.degree..+-.0.3.degree.. In a particular embodiment, polymorph
Ia is characterized by an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2-Theta at angles of
4.8.degree..+-.0.3.degree., 8.9.degree..+-.0.3.degree.,
11.3.degree..+-.0.3.degree., 14.9.degree..+-.0.3.degree.,
18.0.degree..+-.0.3.degree., 19.4.degree..+-.0.3.degree.,
21.3.degree..+-.0.3.degree. 22.8.degree..+-.0.3.degree. and
24.3.degree..+-.0.3.degree..
[0037] In still another embodiment, polymorph Ia is characterized
by an X-ray powder diffraction pattern having 6-9 peaks expressed
in degrees 2-Theta at angles selected from
8.9.degree..+-.0.2.degree., 18.0.degree..+-.0.2.degree.,
21.3.degree..+-.0.2.degree., 4.8.degree..+-.0.2.degree.,
11.3.degree..+-.0.2.degree., 14.9.degree..+-.0.2.degree.,
19.4.degree..+-.0.2.degree., 22.8.degree..+-.0.2.degree. and
24.3.degree..+-.0.2.degree.. In a particular embodiment, polymorph
Ia is characterized by an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2-Theta at angles of
4.8.degree..+-.0.2.degree., 8.9.degree..+-.0.2.degree.,
11.3.degree..+-.0.2.degree., 14.9.degree..+-.0.2.degree.,
18.0.degree..+-.0.2.degree., 19.4.degree..+-.0.2.degree.,
21.3.degree..+-.0.2.degree. 22.8.degree..+-.0.2.degree. and
24.3.degree..+-.0.2.degree..
[0038] In still another embodiment, provided herein is a
composition comprising crystalline tazobactam arginine
characterized by an X-ray powder diffraction pattern having peaks
expressed in degrees 2-Theta.+-.0.3.degree. at angles of
4.8.degree., 8.9.degree., 11.3.degree., 14.9.degree., 18.0.degree.,
19.4.degree., 21.3.degree., 22.8.degree. and 24.3.degree..
[0039] In still another embodiment, provided herein is a
composition comprising crystalline tazobactam arginine
characterized by an X-ray powder diffraction pattern having peaks
expressed in degrees 2-Theta.+-.0.2.degree. at angles of
4.8.degree., 8.9.degree., 11.3.degree., 14.9.degree., 18.0.degree.,
19.4.degree., 21.3.degree., 22.8.degree. and 24.3.degree..
[0040] In still another embodiment, provided herein is a
composition comprising crystalline tazobactam arginine
characterized by an X-ray powder diffraction pattern having peaks
expressed in degrees 2-Theta.+-.0.1.degree. at angles of
4.8.degree., 8.9.degree., 11.3.degree., 14.9.degree., 18.0.degree.,
19.4.degree., 21.3.degree., 22.8.degree. and 24.3.degree..
[0041] In still another embodiment, provided herein is a
composition comprising crystalline tazobactam arginine
characterized by an X-ray powder diffraction pattern having peaks
expressed in degrees 2-Theta at angles of about 4.8.degree.,
8.9.degree., 11.3.degree., 14.9.degree., 18.0.degree.,
19.4.degree., 21.3.degree., 22.8.degree. and 24.3.degree..
[0042] In one embodiment, polymorph Ia is characterized by an X-ray
powder diffraction pattern having peaks substantially in accordance
with FIG. 1. In another embodiment, polymorph Ia is characterized
by an X-ray powder diffraction pattern having peaks substantially
in accordance with Table 1.
[0043] The compounds of the invention may also be defined by their
differential scanning calorimetry (DSC) thermograms. In one
embodiment, polymorph Ia is characterized by a differential
scanning calorimetry thermogram having a characteristic peak
expressed in units of .degree. C. at a temperature of 209.2.+-.3.
In a particular embodiment, polymorph Ia is characterized by a
differential scanning calorimetry thermogram substantially in
accordance with FIG. 2.
[0044] The compounds of the invention can be also be defined by
their thermogravimetry (TG) signals. In one embodiment, polymorph
Ia is characterized by a thermogravimetry curve with an onset
temperature of 201.8.degree. C..+-.3.degree. C. In a particular
embodiment, polymorph Ia is characterized by a thermogravimetry
curve substantially in accordance with FIG. 3.
[0045] In certain embodiments, polymorph Ia may contain impurities.
Non-limiting examples of impurities include undesired polymorph
forms, or residual organic and inorganic molecules such as
solvents, water or salts.
[0046] In another embodiment, polymorph Ia is substantially free
from impurities. In another embodiment, polymorph Ia contains less
than 10% by weight total impurities. In another embodiment,
polymorph Ia contains less than 5% by weight total impurities. In
another embodiment, polymorph Ia contains less than 1% by weight
total impurities. In yet another embodiment, polymorph Ia contains
less than 0.1% by weight total impurities.
[0047] In another aspect, provided herein is crystalline tazobactam
arginine polymorph Ib. In one embodiment, polymorph Ib is
tazobactam arginine trihydrate. In another embodiment, crystalline
tazobactam polymorph Ib is characterized by an X-ray powder
diffraction pattern having peaks expressed in degrees 2-Theta at
angles of 4.4.degree..+-.0.3.degree., 9.7.degree..+-.0.3.degree.,
17.3.degree..+-.0.3.degree., 20.2.degree..+-.0.3.degree., and
22.0.degree..+-.0.3.degree.. In a particular embodiment, polymorph
Ib is characterized by an X-ray powder diffraction pattern having
peaks substantially in accordance with FIG. 4.
[0048] In another aspect, provided herein is a composition
comprising one or more compounds selected from amorphous tazobactam
arginine, polymorph Ia and polymorph Ib. In one embodiment, the
composition comprises one or more compounds selected from
tazobactam arginine and polymorph Ia.
[0049] In certain embodiments, polymorph Ia is a crystalline solid
substantially free of amorphous tazobactam arginine. As used
herein, the term "substantially free of amorphous tazobactam
arginine" means that the compound contains no significant amount of
amorphous tazobactam arginine. In certain embodiments, at least
about 95% by weight of crystalline polymorph Ia is present. In
still other embodiments of the invention, at least about 99% by
weight of crystalline polymorph Ia is present.
[0050] In another embodiment, polymorph Ia is substantially free
from polymorph Ib. As used herein, the term "substantially free of
polymorph Ib "means that the compound contains no significant
amount of polymorph Ib. In certain embodiments, at least about 95%
by weight of crystalline polymorph Ia is present. In still other
embodiments of the invention, at least about 99% by weight of
crystalline polymorph Ia is present.
Processes and Methods
[0051] Provided herein is a method of making crystalline tazobactam
arginine comprising:
[0052] (1) combining tazobactam acid, arginine and a solvent, such
that a solution of tazobactam arginine is formed; and
[0053] (2) combining an antisolvent with the solution, wherein the
antisolvent is miscible with the solvent and wherein tazobactam
arginine is partially or completely insoluble in the antisolvent,
such that crystalline tazobactam arginine precipitates from the
solution.
[0054] In step (1), tazobactam acid may first be combined with the
solvent, and the resulting mixture then combined with arginine.
Alternatively, arginine may first be combined with the solvent, and
the resulting mixture then combined with tazobactam acid.
Alternatively, tazobactam acid and arginine may be combined, and
the resulting mixture then combined with the solvent.
[0055] In one embodiment, the above method is a method of making
tazobactam arginine polymorph Ia, said method further comprising:
(3) drying the precipitated crystalline tazobactam arginine to
afford polymorph Ia.
[0056] In one embodiment, the antisolvent is added to the solution
of tazobactam arginine. In another embodiment, the solution of
tazobactam argine is added to the antisolvent. In certain
embodiments, the solvent is selected from the group consisting of
water and acetic acid. In certain embodiments, the antisolvent is
selected from the group consisting of alcohols, ethers, esters,
ketones, nitriles, amides, nitroalkanes, nitroarenes, substituted
or unsubstituted aromatic solvents, substituted or unsubstituted
aliphatic solvents and mixtures thereof. In certain embodiments,
the antisolvent is selected from the group consisting of acetone,
acetonitrile, 1-butanol, cyclohexane, dichloromethane, diisopropyl
ether, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, ethanol,
ethyl acetate, heptanes, methanol, isopropyl acetate, methyl ethyl
ketone, methyl isobutyl ketone, N-methyl-2-pyrrolidinone,
nitromethane, 2-propanol, tert-butylmethyl ether, tetrahydrofuran,
toluene and mixtures thereof. Experiments determining solubility of
crystalline tazobactam arginine in a variety of solvents are
described in Experiment 6, and results are summarized in Table 3.
In a preferred embodiment, the solvent is water. In another
preferred embodiment, the antisolvent is acetone. In yet another
preferred embodiment, the antisolvent is isopropanol.
[0057] Accordingly, provided herein is a method of making
crystalline tazobactam arginine comprising:
[0058] (1) combining tazobactam acid, arginine and water, such that
an aqueous solution of tazobactam arginine is formed; and
[0059] (2) combining acetone with the aqueous solution, such that
crystalline tazobactam arginine precipitates from the solution.
[0060] In one embodiment, the above method is a method of making
tazobactam arginine polymorph Ia, said method further comprising:
(3) drying the precipitated crystalline tazobactam arginine to
afford polymorph Ia.
[0061] In another aspect, provided herein is a method of making
crystalline tazobactam arginine (e.g., polymorph Ia)
comprising:
[0062] (1) combining tazobactam arginine and a solvent, such that a
solution of tazobactam arginine is formed; and
[0063] (2) combining an antisolvent with the solution, wherein the
antisolvent is miscible with the solvent and wherein tazobactam
arginine is partially or completely insoluble in the antisolvent,
such that crystalline tazobactam arginine precipitates from the
solution.
[0064] In another aspect, provided herein is a method of making
crystalline tazobactam arginine comprising:
[0065] (1) combining tazobactam acid, arginine and a
solvent/antisolvent mixture, such that a solution of tazobactam
arginine is formed; and
[0066] (2) combining an antisolvent with the solution, wherein the
antisolvent is miscible with the solvent and wherein tazobactam
arginine is partially or completely insoluble in the antisolvent,
such that crystalline tazobactam arginine precipitates from the
solution.
[0067] In certain embodiments, any one of the above methods is a
method of making tazobactam arginine polymorph Ia and the method
further comprises: (3) drying the precipitated crystalline
tazobactam arginine to afford polymorph Ia.
[0068] In another aspect, provided herein is a method of making
crystalline tazobactam arginine comprising:
[0069] (1) combining a compound according to formula (I), a
compound according to formula (II), and a solvent, such that a
solution comprising tazobactam arginine is formed, and such that
crystalline tazobactam arginine precipitates from the solution.
##STR00003##
[0070] In one embodiment, Y is a metal atom or ion and X- is a
halide ion.
[0071] In still another aspect, provided herein is a method of
making crystalline tazobactam arginine comprising:
[0072] (1) combining a compound according for formula (I), a
compound according to formula (II), and a solvent, such that a
solution comprising tazobactam arginine is formed; and
[0073] (2) combining an antisolvent with the solution, wherein the
antisolvent is miscible with the solvent and wherein tazobactam
arginine is partially or completely insoluble in the antisolvent,
such that crystalline tazobactam arginine precipitates from the
solution. In one embodiment, Y is a metal atom or ion and X- is a
halogen ion.
[0074] In another aspect, provided herein is crystalline tazobactam
arginine produced according to the any one of the preceding
methods. In another aspect, provided herein is crystalline
tazobactam arginine obtainable by any one of the preceding
methods.
[0075] The processes and methods described herein may also further
comprise adding one or more seed crystals of crystalline tazobactam
arginine (e.g., polymorph Ia or polymorph Ib).
[0076] As used herein, the verb "precipitate" refers to the
formation of a solid substance from a solution containing the same
substance. A substance which precipitates from solution may be
amorphous or crystalline. Precipitation may occur under a variety
of conditions known to those of skill in the art, including the
treatment of a solution of a solute (e.g., solute A in solvent B)
with an antisolvent (i.e., a solvent that is miscible with solvent
B, but does not dissolve solute A). Non-limiting examples of
solvent/antisolvent pairs include water/acetone and
water/isopropanol.
Pharmaceutical Compositions
[0077] In one aspect, provided herein is a pharmaceutical
composition comprising tazobactam arginine polymorph Ia.
[0078] In another aspect, provided herein is a pharmaceutical
composition comprising crystalline tazobactam arginine, hydrates or
solvates thereof, and one or more beta-lactam compounds, and a
pharmaceutically acceptable carrier or diluent. In one embodiment,
the pharmaceutical composition is useful for treating a bacterial
infection. The bacterial infection can result from either
gram-negative or gram-positive organisms. In one embodiment, the
crystalline tazobactam arginine is polymorph Ia. Polymorph Ia is
characterized as described above.
[0079] In yet another aspect, provided herein is a pharmaceutical
composition prepared by a method comprising the step of combining
crystalline tazobactam arginine, or hydrates or solvates thereof,
and a beta-lactam compound. In one embodiment, the crystalline
tazobactam arginine is polymorph Ia. Polymorph Ia is characterized
as described above.
[0080] A "beta-lactam compound" is a compound possessing one or
more beta-lactam moieties, i.e.,
##STR00004##
substituted one or more times as valency permits. In certain
non-limiting embodiments the beta-lactam compounds described herein
can be selected from the group consisting of penicillins,
cephalosporins, carbapenems, and combinations thereof. In certain
embodiments, said one or more beta-lactam compounds are selected
from the compounds listed in Table 2, and pharmaceutically
acceptable isomers, salts, esters, hydrates, solvates, or
combinations thereof.
[0081] The following compounds are listed in Table 2: [0082]
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c acid; [0083]
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.-
2.0]heptane-2-carboxylic acid; [0084]
(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-o-
xo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; [0085]
(5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia--
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; [0086]
(2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-3,3--
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;
[0087]
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acet-
amido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-
e-2-carboxylate; [0088]
6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)ace-
tamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid; [0089]
(6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiaz-
ol-3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]s-
ulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
[0090]
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-met-
hylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-
-carboxylate; [0091]
(6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimi-
no)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid; [0092]
(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amin-
o}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]meth-
yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
[0093]
(2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethy-
l-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; [0094]
3-[5-(dimethylcarbamoyl)
pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3-
.2.0]hept-2-ene-2-carboxylic acid.
[0095] In a particular embodiment, the pharmaceutical composition
comprises polymorph Ia and
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.-
2.0]heptane-2-carboxylic acid or a pharmaceutically acceptable
isomer, salt, ester, hydrate, solvate, or combination thereof, and
a pharmaceutically acceptable carrier or diluent.
[0096] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-o-
xo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof, and a pharmaceutically acceptable carrier
or diluent.
[0097] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia--
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof, and a pharmaceutically acceptable carrier
or diluent.
[0098] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-3,3--
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,
or a pharmaceutically acceptable isomer, salt, ester, hydrate,
solvate, or combination thereof, and a pharmaceutically acceptable
carrier or diluent.
[0099] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acet-
amido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-
e-2-carboxylate, or a pharmaceutically acceptable isomer, salt,
ester, hydrate, solvate, or combination thereof, and a
pharmaceutically acceptable carrier or diluent.
[0100] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)ac-
etamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof, and a pharmaceutically
acceptable carrier or diluent.
[0101] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-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, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof, and a pharmaceutically acceptable carrier
or diluent.
[0102] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-met-
hylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-
-carboxylate, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof, and a pharmaceutically
acceptable carrier or diluent.
[0103] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimi-
no)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof, and a pharmaceutically
acceptable carrier or diluent.
[0104] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amin-
o}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]meth-
yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or
a pharmaceutically acceptable isomer, salt, ester, hydrate,
solvate, or combination thereof, and a pharmaceutically acceptable
carrier or diluent.
[0105] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethy-
l-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof, and a pharmaceutically acceptable carrier
or diluent.
[0106] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c acid, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof, and a pharmaceutically
acceptable carrier or diluent.
[0107] In another particular embodiment, the pharmaceutical
composition comprises polymorph Ia and
3-[5-(dimethylcarbamoyl)pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-met-
hyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof, and a pharmaceutically acceptable carrier
or diluent.
[0108] Pharmaceutical compositions comprising compounds of the
invention can be identified by comparison of the compositions'
X-ray powder diffraction patterns to an X-ray powder diffraction
pattern of a compound of the invention. It will be appreciated that
pharmaceutical compositions comprising a compound of the invention
may exhibit non-identical X-ray powder diffraction patterns as
compared to an X-ray powder diffraction pattern of a pure compound
of the invention.
[0109] The term "pharmaceutical composition" includes preparations
suitable for administration to mammals, e.g., humans. When the
compounds of the present invention are administered as
pharmaceuticals to mammals, e.g., humans, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1% to
99.9% (more preferably, 0.5 to 90%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0110] The pharmaceutical compositions described herein can be
formulated to have any concentration desired (i.e., any
concentration of crystalline tazobactam arginine, or a hydrate or
solvate thereof, and any concentration of a beta-lactam compound).
In some embodiments, the composition is formulated such that it
comprises at least a therapeutically effective amount of both
compounds (i.e., a therapeutically effective amount of the
combination of crystalline tazobactam arginine, or a hydrate or
solvate thereof, and the beta-lactam compound). In some
embodiments, the composition is formulated such that it would not
cause one or more unwanted side effects.
[0111] The compounds of the invention (i.e., polymorphs, hydrates
and solvates of tazobactam arginine) can be combined with a
pharmaceutically acceptable carrier according to conventional
pharmaceutical compounding techniques. As used herein,
"pharmaceutically acceptable carrier" may include any and all
solvents, diluents, or other liquid vehicle, dispersion or
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants and
the like, as suited to the particular dosage form desired.
Remington's Pharmaceutical Sciences, Eighteenth Edition, A. R.
Gennaro (Mack Publishing Co., Easton, Pa., 1990) discloses various
carriers used in formulating pharmaceutical compositions and known
techniques for the preparation thereof. Except insofar as any
conventional carrier medium is incompatible with the compounds such
as by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutical composition, its use is contemplated to be
within the scope of this invention. Some examples of materials
which can serve as pharmaceutically acceptable carriers include,
but are not limited to, sugars such as lactose, glucose and
sucrose; starches such as corn starch and potato starch; cellulose
and its derivatives such as sodium carboxymethyl cellulose, ethyl
cellulose and cellulose acetate; powdered tragacanth; malt;
gelatine; talc; excipients such as cocoa butter and suppository
waxes; oils such as peanut oil, cottonseed oil; safflower oil,
sesame oil; olive oil; corn oil and soybean oil; glycols; such as
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen free water; isotonic saline
("normal saline"); Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, trehalose, or reducing or
non-reducing sugars, 5% dextrose (D5W), preservatives and
antioxidants can also be present in the composition, according to
the judgment of the formulator.
[0112] Furthermore, the carrier may take a wide variety of forms
depending on the form of the preparation desired for
administration, e.g. oral, nasal, rectal, vaginal, parenteral
(including intravenous injections or infusions). In preparing
compositions for oral dosage form any of the usual pharmaceutical
media may be employed. Usual pharmaceutical media include, for
example, water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents, and the like in the case of oral
liquid preparations (such as for example, suspensions, solutions,
emulsions and elixirs); aerosols; or carriers such as starches,
sugars, microcrystalline cellulose, diluents, granulating agents,
lubricants, binders, disintegrating agents and the like, in the
case of oral solid preparations (such as for example, powders,
capsules, and tablets).
[0113] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0114] Pharmaceutical compositions include those suitable for oral,
sublingual, nasal rectal, vaginal, topical, buccal and parenteral
(including subcutaneous, intramuscular, and intravenous)
administration, although the most suitable route will depend on the
nature and severity of the condition being treated. The
compositions may be conveniently presented in unit dosage form, and
prepared by any of the methods well known in the art of pharmacy.
In certain embodiments, the pharmaceutical composition is
formulated for oral administration in the form of a pill, capsule,
lozenge or tablet. In other embodiments, the pharmaceutical
composition is in the form of a suspension.
[0115] The pharmaceutical compositions disclosed herein can be
prepared via lyophilization. As is known to those skilled in the
art, lyophilization is a process of drying in which water is
sublimed from a frozen solution of one or more solutes. Specific
methods of lyophilization are described in Remington's
Pharmaceutical Sciences, Chapter 84, page 1565, Eighteenth Edition,
A. R. Gennaro, (Mack Publishing Co., Easton, Pa., 1990).
[0116] In a preferred embodiment, pharmaceutical compositions
comprising crystalline tazobactam arginine (e.g., polymorph Ia) and
one or more beta-lactam compounds are formulated for parenteral
administration. In another preferred embodiment, pharmaceutical
compositions comprising tazobactam arginine and one or more
beta-lactam compounds are formulated for oral administration.
Methods of Treatment
[0117] Tazobactam arginine inhibits or decreases the activity of
beta-lactamases (e.g., bacterial beta-lactamases), and can be
combined with beta-lactam compounds (e.g., antibiotics), thereby
broadening the spectrum of the beta-lactam compound and increasing
the beta-lactam compound's efficacy against organisms that produce
beta-lactamase. A compound or a composition possesses efficacy
against an organism if it kills or weakens the organism, or
inhibits or prevents reproduction the organism.
[0118] In one aspect, provided herein is a method for the treatment
of bacterial infections in a mammal, comprising administering to
said mammal a therapeutically effective amount of tazobactam
arginine polymorph Ia.
[0119] In another aspect, provided herein is a method for the
treatment of bacterial infections in a mammal, comprising
administering to said mammal a therapeutically effective amount of
a pharmaceutical composition comprising tazobactam arginine
polymorph Ia.
[0120] In yet another aspect, provided herein is a method for the
treatment of bacterial infections in a mammal, comprising
administering to said mammal a therapeutically effective amount of
a pharmaceutical composition comprising crystalline tazobactam
arginine and one or more beta-lactam compounds, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof. In one embodiment, the mammal is human. In
another embodiment, tazobactam arginine is polymorph Ia. In yet
another embodiment, said one or more beta-lactam compounds are
selected from the group consisting of penicillins, cephalosporins,
carbapenems, and combinations thereof. In certain embodiments, the
beta-lactam compound is selected from the compounds listed in Table
2, and pharmaceutically acceptable isomers, salts, esters,
hydrates, solvates, or combinations thereof.
[0121] The following compounds are listed in Table 2:
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c acid;
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabic-
yclo[3.2.0]heptane-2-carboxylic acid;
(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-o-
xo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia--
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-3,3--
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acet-
amido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-
e-2-carboxylate;
(6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)ac-
etamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid;
(6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-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;
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-met-
hylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-
-carboxylate;
(6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimi-
no)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid;
(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acety-
l]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thi-
o]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid;
(2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethy-
l-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;
3-[5-(dimethylcarbamoyl)pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-met-
hyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
[0122] In a particular embodiment of the method, the pharmaceutical
composition comprises polymorph Ia and
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.-
2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable
isomer, salt, ester, hydrate, solvate, or combination thereof.
[0123] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-o-
xo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof.
[0124] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia--
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof.
[0125] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-3,3--
dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,
or a pharmaceutically acceptable isomer, salt, ester, hydrate,
solvate, or combination thereof.
[0126] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acet-
amido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-
e-2-carboxylate, or a pharmaceutically acceptable isomer, salt,
ester, hydrate, solvate, or combination thereof.
[0127] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)ac-
etamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof.
[0128] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(6R,7R)-7-R2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-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, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof.
[0129] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-met-
hylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-
-carboxylate, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof.
[0130] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimi-
no)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof.
[0131] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amin-
o}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]meth-
yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or
a pharmaceutically acceptable isomer, salt, ester, hydrate,
solvate, or combination thereof.
[0132] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethy-
l-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof.
[0133] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
3-[5-(dimethylcarbamoyl)pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-met-
hyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a
pharmaceutically acceptable isomer, salt, ester, hydrate, solvate,
or combination thereof.
[0134] In another particular embodiment of the method, the
pharmaceutical composition comprises polymorph Ia and
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c acid, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof. In another particular
embodiment, the bacterial infection is caused by bacteria that are
susceptible to the composition comprising polymorph Ia and
(2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenyla-
cetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxyli-
c acid, or a pharmaceutically acceptable isomer, salt, ester,
hydrate, solvate, or combination thereof.
[0135] In another aspect, provided herein is a method for the
treatment of bacterial infections in a mammal, comprising
administering to said mammal a therapeutically effective amount of
a pharmaceutical composition comprising an antibiotic and a
crystalline tazobactam arginine compound (e.g., of the polymorph Ia
solid form). The crystalline tazobactam arginine can be
characterized by an X-ray powder diffraction pattern having peaks
expressed in degrees 2-Theta at angles of
4.8.degree..+-.0.3.degree., 8.9.degree..+-.0.3.degree.,
11.3.degree..+-.0.3.degree., 14.9.degree..+-.0.3.degree.,
18.0.degree..+-.0.3.degree., 19.4.degree..+-.0.3.degree.,
21.3.degree..+-.0.3.degree., 22.8.degree..+-.0.3.degree. and
24.3.degree..+-.0.3.degree..
[0136] Non-limiting examples of bacterial infections that can be
treated by the methods of the invention include infections caused
by: aerobic and facultative gram-positive microorganisms (e.g.,
Staphylococcus aureus, Enterococcus faecalis, Staphylococcus
epidermidis, Streptococcus agalactiae, Streptococcus pneumonia,
Streptococcus pyogenes, Viridans group streptococci), aerobic and
facultative gram-negative microorganisms (e.g., Acinetobacter
baumanii, Escherichia coli, Haemophilus influenza, Klebsiella
pneumonia, Pseudomonas aeruginosa, Citrobacter koseri, Moraxella
catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus
mirabilis, Proteus vulgaris, Serratia marcescens, Providencia
stuartii, Providencia rettgeri, Salmonella enterica), gram-positive
anaerobes (Clostridium perfringens), and gram-negative anaerobes
(e.g., Bacteroides fragilis group (e.g., B. fragilis, B. ovatus, B.
thetaiotaomicron, and B. vulgates), Bacteroides distasonis,
Prevotella melaninogenica).
[0137] In certain embodiments of the methods described herein,
bacterial infection resulting from beta-lactamase-producing
organisms are treated or controlled. Non-limiting examples of
beta-lactamase-producing organisms include:
[0138] (1) ESBL (extended-spectrum beta-lactamase)-producing
organisms selected from the group consisting of Enterobacteriaceae
spp.: Escherichia coli, Klebsiella spp. (including K. pneumoniae
and K. oxytoca), Proteus mirabilis, Proteus vulgaris, Enterobacter
spp., Serratia spp., Citrobacter spp., Pseudomonas spp.,
Acinetobacter spp.) and Bacteroides spp.;
[0139] (2) CSBL (conventional-spectrum beta-lactamase)-producing
organisms, known to those of skill in the art; and
[0140] (3) Inducible-AmpC-type beta-lactamases, such as Citrobacter
spp., Serratia spp., Morganella morganii, Proteus vulgaris, and
Enterobacter cloacae.
[0141] In certain embodiments of the methods described herein,
bacterial infection is associated with one or more of the following
conditions:
[0142] Appendicitis (complicated by rupture or abscess) and
peritonitis caused by piperacillin-resistant beta-lactamase
producing strains of Escherichia coli or the following members of
the Bacteroides fragilis group: B. fragilis, B. ovatus, B.
thetaiotaomicron, or B. vulgates;
[0143] Uncomplicated and complicated skin and skin structure
infections, including cellulitis, cutaneous abscesses, and
ischemic/diabetic foot infections caused by piperacillin-resistant,
beta-lactamase producing strains of Staphylococcus aureus;
[0144] Postpartum endometritis or pelvic inflammatory disease
caused by piperacillin-resistant, beta-lactamase producing strains
of Escherichia coli;
[0145] Community-acquired pneumonia (moderate severity only) caused
by piperacillin-resistant, beta-lactamase producing strains of
Haemophilus influenza;
[0146] Nosocomial pneumonia (moderate to severe) caused by
piperacillin-resistant, beta-lactamase producing strains of
Staphylococcus aureus and by Acinetobacter baumanii, Haemophilus
influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
[0147] Complicated intra-abdominal infections; Complicated urinary
tract infections (cUTIs); Acute Pyelonephritis; Systemic
Inflammatory Response Syndrome (SIRS).
[0148] Also provided herein is the use of a crystalline tazobactam
arginine, and hydrates and solvates thereof, in combination with
one or more beta-lactam compounds, for the manufacture of a
medicament for the treatment of bacterial infection. The bacterial
infection can result from either gram-negative or gram-positive
organisms. In one embodiment, the crystalline tazobactam arginine
is polymorph Ia. Polymorph Ia is characterized as described above.
Said one or more beta-lactam compounds can be selected from the
group consisting of penicillins, cephalosporins, carbapenems, and
combinations thereof. In certain embodiments, said one or more
beta-lactam compounds are selected from the compounds listed in
Table 2, and pharmaceutically acceptable isomers, salts, esters,
hydrates, solvates, or combinations thereof.
[0149] Also provided herein is tazobactam arginine, and hydrates
and solvates thereof, for use in a method of treating bacterial
infection. In some embodiments, a combination of tazobactam
arginine and one or more beta-lactam compounds is used in said
method.
[0150] As used herein, "treating", "treat" or "treatment" describes
the management and care of a patient for the purpose of combating a
disease, condition, or disorder and includes the administration of
a pharmaceutical composition of the present invention to alleviate
the symptoms or complications of a disease, condition or disorder,
or to eliminate the disease, condition or disorder. The term
"treat" can also include treatment of a cell in vitro or an animal
model.
[0151] By a "therapeutically effective amount" of a compound of the
invention is meant a sufficient amount of the compound to treat the
disorder (e.g., bacterial infection). The specific therapeutically
effective amount that is required for the treatment of any
particular patient or organism (e.g., a mammal) will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; the activity of the specific compound or
composition employed; the specific composition employed; the age,
body weight, general health, sex and diet of the patient; the time
of administration, route of administration, and rate of excretion
of the specific compound employed; the duration of the treatment;
drugs used in combination or coincidental with the specific
compound employed; and like factors well known in the medical arts
(see, for example, Goodman and Gilman's, "The Pharmacological Basis
of Therapeutics", Tenth Edition, A. Gilman, J. Hardman and L.
Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is
incorporated herein by reference in its entirety). The
therapeutically effective amount for a given situation can be
readily determined by routine experimentation and is within the
skill and judgment of the ordinary clinician.
Assays
[0152] Provided herein is a method for detecting or identifying an
agent that will inhibit one or more beta-lactamase-producing
organisms, said method comprising combining:
[0153] (a) a test agent;
[0154] (b) a composition comprising one or more
beta-lactamase-producing organisms; and
[0155] (c) a beta-lactamase inhibitor; and
[0156] detecting or measuring a change in the activity of the
beta-lactamase-producing organisms, wherein a decrease in the
activity of the beta-lactamase-producing organisms indicates that
the test agent inhibits the beta-lactamase-producing organisms.
[0157] As used in the above method, "activity" refers to the
ability of the beta-lactamase-producing organism to reproduce
and/or infect another organism, or "activity" refers to the
presence of an indicator of the ability of the
beta-lactamase-producing organism to reproduce and/or infect
another organism. Methods for detecting and/or measuring changes in
the activity of beta-lactamase-producing organisms are known to
those of skill in the art.
[0158] In another aspect, provided herein is a method of
determining the susceptibility of a beta-lactamase-producing
organism to a composition comprising a beta-lactam compound and a
beta-lactamase inhibitor. The in vitro activity of compositions of
the subject invention may be assessed by standard testing
procedures. Non-limiting examples of such a procedure include the
Kirby-Bauer method, the Stokes test, the E-test, broth dilution and
agar dilution for determination of minimum inhibitory concentration
(MIC), as described in "Approved Standard. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow
Aerobically," 3.sup.rd ed., published 1993 by the National
Committee for Clinical Laboratory standards, Villanova, Pa., USA.
In certain embodiments, the methods described herein are performed
using automation (e.g., Siemens' MicroScan Systems).
[0159] In one embodiment of the above methods, the beta-lactamase
inhibitor is tazobactam arginine. In a preferred embodiment, the
beta-lactamase inhibitor is tazobactam arginine polymorph Ia.
[0160] The test agent can be selected from the group consisting of
penicillins, cephalosporins, carbapenems, and combinations thereof.
In some embodiments, the test agent is selected from the compounds
listed in Table 2, and pharmaceutically acceptable isomers, salts,
esters, hydrates, solvates, or combinations thereof.
[0161] In certain embodiments of the methods described herein,
beta-lactamase-producing organisms are selected from the group
comprising:
[0162] (1) ESBL (extended-spectrum beta-lactamase)-producing
organisms selected from the group consisting of Enterobacteriaceae
spp.: Escherichia coli, Klebsiella spp. (including K. pneumoniae
and K. oxytoca), Proteus mirabilis, Proteus vulgaris, Enterobacter
spp., Serratia spp., Citrobacter spp.) and Bacteroides spp.;
[0163] (2) CSBL (conventional-spectrum beta-lactamase)-producing
organisms, known to those of skill in the art; and
[0164] (3) Inducible-AmpC-type beta-lactamases, such as Citrobacter
spp., Serratia spp., Morganella morganii, Proteus vulgaris, and
Enterobacter cloacae.
EXAMPLES
Example 1
Preparation of Tazobactam Arginine Amorphous
[0165] L-arginine (2.9 g) was dissolved in 100 mL of deionized
water and 5.0 g of tazobactam acid was then added, resulting a
homogenous solution. The solution was lyophilized overnight to
yield tazobactam arginine amorphous as an off-white solid (8.0 g).
The XRPD spectrum of the tazobactam arginine amorphous is depicted
in FIG. 5.
Example 2
Preparation of Tazobactam Arginine Crystalline Polymorph Ia
[0166] Tazobactam arginine amorphous (1.00 g) was dissolved in 10.0
mL of deionized water. 30 mL of acetone was added to the aqueous
solution by drop-wise addition. The mixture was allowed to sit
overnight at ambient temperature, resulting in white fine needles.
After filtration and vacuum drying for 4 hours, tazobactam arginine
polymorph Ia (516 mg) was obtained. The XRPD spectrum of the
tazobactam arginine polymorph Ia is depicted in FIG. 1.
Example 3
Preparation of Tazobactam Arginine Crystalline Polymorph Ia
[0167] L-arginine (1.16 g) was charged to the reactor and dissolved
in a mixture of deionized water-acetone (1:1, v/v, 40 mL) by
mechanically stirring at 300 rpm, 30.degree. C. over 5 min.
Tazobactam acid (2.00 g) was then added to the above solution over
2 min with the observed pH change from 10.5.+-.0.5 to 5.9.+-.0.5.
After adding 34.5 mL of acetone over 30 min at 30.degree. C.,
crystallization started, then the suspension was cooled down to
15.degree. C. at 0.1.degree. C./min and kept stirring at 15.degree.
C. for additional 1.5 hr. White fine needle crystals were filtered
out and vacuum dried for 2 hours at 35.degree. C. to obtain 2.59 g
(82% yield) of tazobactam arginine polymorph Ia.
Example 4
Preparation of Tazobactam Arginine Crystalline Polymorph Ia--20 g
Scale
[0168] 1) 20 g of tazobactam acid and 1 equivalent of L-arginine
was placed into a jacketed, glass, 1 liter laboratory reactor with
an overhead stirrer. [0169] 2) 5 volumes (relative to tazobactam
acid weight) of ambient temperature (ca. 22.degree. C.) water was
added to the reactor and stirred at 480 rpm. The reactor
temperature was maintained between 23-27.degree. C. with a target
temperature of 25.degree. C. The reaction was stirred for 10-15
minutes in order to obtain complete dissolution. Stirring at 480
rpm was maintained throughout the reaction. [0170] 3) 0.75 vol.
ambient temperature deionised water was added to the reactor. This
step was included to account for the sterile filtration and washing
step required in the process. [0171] 4) 8 volumes (160 ml) of
acetone was added over 10 minutes. [0172] 5) The reaction mixture
was aged for 15 minutes, at which point precipitation of tazobactam
arginine begins. [0173] 6) A controlled cool was started from
25.degree. C. down to 10.degree. C. over 1.5 hours at a rate of
10.degree. C./hour. [0174] 7) After reaching 10.degree. C., 18
volumes of acetone was added over two hours (i.e., total acetone
added throughout reaction was 26 volumes). [0175] 8) After the
acetone addition, the reaction mixture was allowed to age for 1
hour. [0176] 9) The reaction mixture was filtered and washed with 5
volumes of cold acetone (ca. 4.degree. C.). [0177] 10) The
resulting solid was dried at ambient (ca. 22.degree. C.) under
vacuum and nitrogen bleed for 24 hours with regular mixing of the
solid, to furnish polymorph Ia in 90% yield. The XRPD spectrum of
the tazobactam arginine polymorph Ia is depicted in FIG. 6.
[0178] The .sup.1H-NMR spectrum (FIG. 7) of polymorph Ia indicates
a stoichiometry of 1:1 tazobactam acid:arginine.
Example 5
Preparation of Tazobactam Arginine Polymorph Ia--Isopropanol
Antisolvent
[0179] 1) 20 g of tazobactam acid and 1 equivalent of L-arginine
was placed into a 1 liter reactor. [0180] 2) 5 volumes (ca. 100 ml)
of water (relative to tazobactam acid weight) was added to the
reactor and stirred at 300 rpm (25.degree. C.) for 10-15 minutes in
order to obtain complete dissolution. [0181] 3) A further 0.75 vol
water was then added to account for washing in sterile filtration
step. [0182] 4) 6 volumes (120 ml) of ispopropanol was added over
ca. 15 minutes in order to initiate precipitation. [0183] 5) The
suspension was then aged for 15 minutes before cooling down to
10.degree. C. over 1.5 hours at a rate of 10.degree. C./hour.
[0184] 6) After reaching 10.degree. C., isopropanol addition was
started at a rate of 185 ml/hour, adding a further 16 volumes
(i.e., total isopropanol added throughout reaction was 24 volumes).
[0185] 7) The reaction was then allowed to age for 1 hour. [0186]
8) The suspension was filtered and washed with 5 volumes of cold
isopropanol (ca. 4.degree. C.). [0187] 9) The resulting solid was
then dried at ambient under vacuum and nitrogen bleed for 24 hours
with regular mixing of the solids to yield tazobactam arginine
crystalline polymorph Ia.
Example 6
Hygroscopicity Experiments
[0188] Analysis by DVS was performed on a VTI SGA-100 water vapor
sorption analyser using approximately 18-23 mg of each sample. Each
sample was pre-dried at 60.degree. C. for a maximum of 1 hour and
then analyzed at 25.degree. C. in 10% relative humidity (RH) steps
from 5-95% (adsorption) and then 90-10% RH (desorption). The sample
was equilibrated to each humidity level for a maximum of 3 hours or
until constant weight was attained. Equilibrium criteria were set
at less than 0.0050% weight change within 5 minutes.
[0189] (6a) Tazobactam arginine amorphous exhibited approximately
10.7% weight increase at 95% relative humidity (RH). See FIG.
8.
[0190] (6b) Tazobactam arginine polymorph Ia exhibited
approximately 0.2% weight increase at 95% RH. See FIG. 9.
[0191] (6c) Amorphous tazobactam sodium exhibited approximately 80%
weight increase at 95% RH. See FIG. 10.
Example 7
Solvent Solubility Screen
[0192] The solvent solubility screen was carried out using a
solvent addition technique. For each of 25 solvent systems, the
following procedure was used: (1) about 20 mg of crystalline
tazobactam arginine was placed into a vial; (2) solvent was added
to the vial in 5 volume aliquots (100 .mu.L) until complete
dissolution, or 100 volumes, had been added; (3) between additions,
the sample was heated to about 50.degree. C. in order to determine
the approximate solubility at an elevated temperature; (4) if 100
volumes was reached and complete dissolution was not observed,
solubility was calculated to be below that point. Results of the
solvent solubility screen are shown in Table 3.
Instrumentation and Methods
[0193] I. X-Ray Powder Diffraction (XRPD) experiments were
performed using a Bruker D8 Advance X-ray powder diffractometer
utilizing a zero return silicon plate. A suitable amount of sample
was placed directly on the sample holder, pressed flat to smooth,
and analyzed from 3.degree.-40.degree. 20 using Bragg-Brentano
optics. A step size of 0.01.degree. and a step time of 0.3 sec/step
were utilized. Analysis was started immediately following sample
preparation. [0194] II. Differential Scanning calorimetry (DSC)
experiments were performed on a TA Instruments Q100 instrument. A
temperature range of 40.degree. C. to 300.degree. C. with a ramp
rate of 10.degree. C./minute was utilized. Approximately 1.0 mg of
sample was weighed into a tared aluminum sample pan and sealed
hermetically. A small hole was pushed into the cover of the sample
pan to allow for pressure release. [0195] III. Thermo Gravimetric
Analysis (TGA) experiments were performed on a TA Instruments 5000
instrument from 20 to 300.degree. C. with a heating rate of
10.degree. C./minute for all samples.
Tables
TABLE-US-00001 [0196] TABLE 1 XRPD Scanning Data of Tazobactam
Arginine Polymorph Ia (FIG. 1) Chord Mid. D (Obs. Intensity Max
Int. Intensity I. Breadth 2-Theta .degree. Angstrom % % Cps Count
2-Theta .degree. 4.818 18.27951 33.5 130 7043 0.166 8.978 9.83463
100.0 364 21035 0.174 9.916 8.90757 8.7 32.3 1832 0.168 11.301
7.81865 27.8 104 5844 0.167 14.521 6.09321 20.2 75.5 4251 0.108
14.902 5.93864 27.8 102 5850 0.162 15.93 5.56039 1.9 7.2 394 0.148
16.947 5.23254 1.2 4.96 253 0.169 17.581 5.04332 6.8 24.8 1429
0.182 18.046 4.91261 48.7 184 10242 0.189 18.863 4.70152 2.6 9.41
545 0.159 19.418 4.5672 31.6 115 6637 0.166 19.943 4.44853 9.3 33.8
1966 0.181 21.31 4.1658 41.4 151 8714 0.192 22.797 3.89704 9.1 33.2
1921 0.201 23.587 3.76939 14.7 53.1 3082 0.171 24.345 3.65381 19.6
71.2 4116 0.208 25.169 3.53603 2.3 8.44 479 0.185 25.895 3.43955
5.4 19.7 1129 0.152 26.221 3.39654 5.0 15.6 1061 0.146 26.689
3.33736 11.1 40 2329 0.192 27.249 3.27088 5.0 19.1 1052 0.25 28.09
3.17445 5.6 20.2 1184 0.269 28.886 3.08881 3.2 11.4 666 0.219
30.129 2.96435 4.2 15.6 884 0.184 30.585 2.92187 1.8 6.17 369 0.313
31.413 2.84617 5.6 20.1 1174 0.212 32.162 2.78029 2.8 9.87 583
0.285 33.878 2.64293 1.1 2.36 236 0.109 34.419 2.60386 3.2 11.5 676
0.239 35.529 2.52408 6.0 21.9 1254 0.344 36.598 2.45267 3.0 11 621
0.269 37.924 2.37119 1.8 6.41 371 0.276 38.818 2.31643 1.4 2.74 295
0.172 39.398 2.28753 1.1 3.56 236 0.196
TABLE-US-00002 TABLE 2 Beta-lactam compounds 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
TABLE-US-00003 TABLE 3 Solvent solubility screen results Solubility
@ 22.degree. C. Solubility @ 50.degree. C. Solvent (mg/ml) (mg/ml)
Acetic acid >100 mg/ml >200 mg/ml Acetone <10 mg/ml <10
mg/ml Acetonitrile <10 mg/ml <10 mg/ml 1-butanol <10 mg/ml
<10 mg/ml Cyclohexane <10 mg/ml <10 mg/ml Dichloromethane
<10 mg/ml <10 mg/ml Diisopropyl ether <10 mg/ml <10
mg/ml Dimethylformamide <10 mg/ml <10 mg/ml Dimethylsulfoxide
<10 mg/ml ca.10 mg/ml 1,4-Dioxane <10 mg/ml <10 mg/ml
Ethanol <10 mg/ml <10 mg/ml Ethyl acetate <10 mg/ml <10
mg/ml Heptane <10 mg/ml <10 mg/ml Methanol <10 mg/ml
<10 mg/ml Isopropyl acetate <10 mg/ml <10 mg/ml Methyl
acetate <10 mg/ml <10 mg/ml Methylethyl ketone <10 mg/ml
<10 mg/ml Methyl isobutyl ketone <10 mg/ml <10 mg/ml
N-Methyl-2-pyrrolidone <10 mg/ml <10 mg/ml Nitromethane
<10 mg/ml <10 mg/ml 2-Propanol <10 mg/ml <10 mg/ml
tert-Butylmethyl ether <10 mg/ml <10 mg/ml Tetrahydrofuran
<10 mg/ml <10 mg/ml Toluene <10 mg/ml <10 mg/ml Water
>100 mg/ml >200 mg/ml
* * * * *