U.S. patent application number 14/289251 was filed with the patent office on 2015-04-02 for solid forms of ceftolozane.
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, Lisa Duong, You Seok Hwang, Valdas Jurkauskas, Kristos Adrian Moshos, Sanjay Mudur, Asli Ovat, Joseph Terracciano, Jason Woertink.
Application Number | 20150094293 14/289251 |
Document ID | / |
Family ID | 52001634 |
Filed Date | 2015-04-02 |
United States Patent
Application |
20150094293 |
Kind Code |
A1 |
Jurkauskas; Valdas ; et
al. |
April 2, 2015 |
SOLID FORMS OF CEFTOLOZANE
Abstract
Novel solid forms of ceftolozane are described, as well as
methods for the preparation and use of these solid forms.
Inventors: |
Jurkauskas; Valdas;
(Cambridge, MA) ; Damour; Nicole Miller; (Belmont,
MA) ; Duong; Lisa; (Lynn, MA) ; Hwang; You
Seok; (Windham, NH) ; Moshos; Kristos Adrian;
(Belmont, MA) ; Mudur; Sanjay; (Woburn, MA)
; Ovat; Asli; (Maynard, MA) ; Terracciano;
Joseph; (Concord, MA) ; Woertink; Jason;
(Sudbury, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CALIXA THERAPEUTICS, INC. |
Lexington |
MA |
US |
|
|
Assignee: |
CALIXA THERAPEUTICS, INC.
Lexington
MA
|
Family ID: |
52001634 |
Appl. No.: |
14/289251 |
Filed: |
May 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61883530 |
Sep 27, 2013 |
|
|
|
Current U.S.
Class: |
514/192 ;
514/207; 544/47 |
Current CPC
Class: |
A61K 47/183 20130101;
A61K 31/546 20130101; A61K 47/12 20130101; A61P 31/04 20180101;
C07D 501/60 20130101; A61K 31/546 20130101; A61P 31/00 20180101;
A61K 9/19 20130101; A61K 31/431 20130101; A61K 31/431 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 9/0019 20130101;
C07D 501/46 20130101 |
Class at
Publication: |
514/192 ; 544/47;
514/207 |
International
Class: |
A61K 31/546 20060101
A61K031/546; A61K 31/431 20060101 A61K031/431 |
Claims
1. A solid form of ceftolozane sulfate that produces an X-ray
powder diffraction (XRPD) pattern having diffractions at angles (2
theta.+-.0.2) of 12.4, 16.4, 22.6, 25.1, and 28.0.
2. The solid form of ceftolozane sulfate of claim 1 that produces
Raman shift peaks (.+-.5 cm.sup.-1) at about 171 cm.sup.-1, 743
cm.sup.-1, 819 cm.sup.-1, 1055 cm.sup.-1, 2894 cm.sup.-1 and 2976
cm.sup.-1.
3. A solid form of ceftolozane sulfate that produces: a. an X-ray
powder diffraction (XRPD) pattern having diffractions at angles (2
theta.+-.0.2) of 24.2 and 37.8 and b. Raman shift peaks (.+-.5
cm.sup.-1) at about 597 cm.sup.-1, 716 cm.sup.-1 and 1329
cm.sup.-1.
4. The solid form of ceftolozane sulfate of claim 3 that produces
an X-ray powder diffraction (XRPD) pattern having additional
diffractions at angles (2 theta.+-.0.2) of 12.4, 16.4, 22.6, 25.1,
and 28.0.
5. The solid form of ceftolozane sulfate of claim 4 that produces
additional Raman shift peaks (.+-.5 cm.sup.-1) at about 171
cm.sup.-1, 743 cm.sup.-1, 819 cm.sup.-1, 1055 cm.sup.-1, 2894
cm.sup.-1 and 2976 cm.sup.-1.
6. The solid form of ceftolozane sulfate of claim 3 that produces
additional Raman shift peaks (.+-.5 cm.sup.-1) at about 171
cm.sup.-1, 743 cm.sup.-1, 819 cm.sup.-1, 1055 cm.sup.-1, 2894
cm.sup.-1 and 2976 cm.sup.-1.
7. A pharmaceutical composition comprising a lyophilized
ceftolozane composition obtained by a process comprising the steps
of: a. combining the ceftolozane sulfate in a solid form designated
as ceftolozane sulfate Form 1, with water, sodium chloride and
L-arginine to form an aqueous solution; and b. lyophilizing the
aqueous solution to form the lyophilized ceftolozane composition
comprising ceftolozane sulfate.
8. The pharmaceutical composition of claim 7, wherein the
lyophilization cycle is characterized by one or more of the
following characteristics: a. not more than 150 mg ceftolozane free
base/g bulk solution concentration, b. no more than 3 cm fill
depth, c. freezing to at least -40.degree. C. during the
lyophilization cycle, d. drying to no more than 40.degree. C., and
e. single- or multi-step drying and setting chamber pressure during
the start of primary drying at not more than 400 .mu.bar.
9. The pharmaceutical composition of claim 8, further comprising
tazobactam.
10. The pharmaceutical composition of claim 9, obtained by a
process further comprising combining the lyophilized ceftolozane
composition with tazobactam in a fixed dose combination providing
about 500 mg of tazobactam active per 1,000 mg of ceftolozane
active in the pharmaceutical composition.
11. A pharmaceutical composition comprising a lyophilized
ceftolozane composition obtained by a process comprising the steps
of: a. combining ceftolozane sulfate in a solid form that produces
an X-ray powder diffraction (XRPD) pattern having diffractions at
angles (2 theta.+-.0.2) of 24.2 and 37.8 and Raman shift peaks
(.+-.5 cm.sup.-1) at about 597 cm.sup.-1, 716 cm.sup.-1 and 1329
cm.sup.-1, with water to form an aqueous solution; and b.
lyophilizing the aqueous solution to form the lyophilized
ceftolozane composition comprising ceftolozane sulfate.
12. A ceftolozane sulfate composition obtained by a process
comprising the steps of: a. forming a solution comprising water,
72-100 g/L ceftolozane active and 1.5-2.95 molar equivalents of
sulfuric acid to ceftolozane; b. combining the solution from step
(a) with 20-40 volumes of isopropyl alcohol added to the solution
over 0.5-8 hours to obtain solid ceftolozane sulfate; and c.
isolating the solid ceftolozane sulfate composition from the
solution.
13. The ceftolozane sulfate composition of claim 12, wherein the
solution comprises 75-85 g/L of ceftolozane active as a
pharmaceutically acceptable ceftolozane salt.
14. The ceftolozane sulfate composition of claim 12, wherein the
solution comprises 2.45-2.55 molar equivalents of sulfuric acid to
ceftolozane active.
15. The ceftolozane sulfate composition of claim 12, wherein the
solution from step (a) is combined with 29-31 volumes of isopropyl
alcohol.
16. The ceftolozane sulfate composition of claim 12, wherein the
solution from step (a) is combined with isopropyl alcohol added to
the solution over 6-7 hours to obtain solid ceftolozane
sulfate.
17. The ceftolozane sulfate composition of claim 12, obtained by a
process wherein: a. the solution comprises water, about 75-85 g/L
ceftolozane active and about 2.45-2.55 molar equivalents of
sulfuric acid to ceftolozane at a temperature of about 5-15 degrees
C.; and b. the solution from step (a) is combined with about 29-31
volumes of isopropyl alcohol added to the solution over about 6-7
hours to obtain solid ceftolozane sulfate.
18. The ceftolozane sulfate composition of claim 12, obtained by a
process further comprising the steps of: a. combining the isolates
solid ceftolozane sulfate with water form a second aqueous
solution; and b. lyophilizing the second aqueous solution to form a
lyophilized ceftolozane pharmaceutical composition comprising
ceftolozane sulfate.
19. The ceftolozane sulfate composition of claim 18, obtained by a
process wherein the second aqueous solution further comprises
sodium chloride and L-arginine.
20. The ceftolozane sulfate composition of claim 18, obtained by a
process further comprising the step of combining the lyophilized
ceftolozane pharmaceutical composition with tazobactam.
21. A method of treating an infection selected from the group
consisting of: complicated intra-abdominal infection (cIAI),
complicated urinary tract infection (cUTI), or hospital
acquired/ventilator-associated bacterial pneumonia (HABP/VABP), the
method comprising the step of administering to a patient an
injectable pharmaceutical composition comprising ceftolozane in an
injectable preparation prepared from a lyophilized composition
obtained by a process comprising the steps of: a. combining the
ceftolozane sulfate in a solid form that produces an X-ray powder
diffraction (XRPD) pattern having diffractions at angles (2
theta.+-.0.2) of 4.4, 8.8, 11.0, 14.9, and 17.7 with water to form
an aqueous solution; and b. lyophilizing the aqueous solution to
form the lyophilized ceftolozane composition comprising ceftolozane
sulfate.
22. A method of manufacturing a ceftolozane sulfate composition,
the method comprising the steps of: a. forming a solution
comprising water, 72-100 g/L ceftolozane active and 1.5-2.95 molar
equivalents of sulfuric acid to ceftolozane; b. combining the
solution from step (a) with 20-40 volumes of isopropyl alcohol
added to the solution over 0.5-8 hours to obtain solid ceftolozane
sulfate; and c. isolating a solid ceftolozane sulfate composition
from the solution.
23. A pharmaceutical composition obtained by a process comprising
the steps of: a. forming aqueous solution comprising sodium
chloride, L-arginine and ceftolozane sulfate in a solid form having
an X-ray powder diffraction (XRPD) pattern having diffractions at
angles (2 theta.+-.0.2) of 24.2 and 37.8 and Raman shift peaks
(.+-.5 cm.sup.-1) at about 597 cm.sup.-1, 716 cm.sup.-1 and 1329
cm.sup.-1; b. lyophilizing the aqueous solution to obtain a
lyophilized ceftolozane composition; c. combining the lyophilized
ceftolozane composition with tazobactam in an amount providing
1,000 mg of ceftolozane active per 500 mg of tazobactam active in
the pharmaceutical composition.
24. The pharmaceutical composition of claim 23, wherein the aqueous
solution comprises about 125-500 mg of sodium chloride per 1,000 mg
of ceftolozane active.
25. The pharmaceutical composition of claim 24, wherein the aqueous
solution has a pH of about 5-7 prior to lyophilization.
26. The pharmaceutical composition of claim 24, wherein the aqueous
solution is lyophilized in the absence of tazobactam.
27. The pharmaceutical composition of claim 24, wherein the
pharmaceutical composition comprises tazobactam sodium and
ceftolozane sulfate.
28. The pharmaceutical composition of claim 24, wherein the
pharmaceutical composition comprises a total of 1,000 mg of
ceftolozane active.
29. The pharmaceutical composition of claim 24, wherein the
pharmaceutical composition is a reconstituted solution obtained by
a process further comprising reconstituting the lyophilized
ceftolozane composition in a pharmaceutically acceptable
liquid.
30. The pharmaceutical composition of claim 29, wherein the
pharmaceutical composition is formulated for intravenous
administration and further comprises 0.9% aqueous sodium chloride
for injection.
31. The pharmaceutical composition of claim 24, wherein the
pharmaceutical composition is a powder for reconstitution prior to
intravenous administration.
32. The pharmaceutical composition of claim 31, wherein the
pharmaceutical composition comprises tazobactam sodium.
33. The pharmaceutical composition of claim 31, wherein the
pharmaceutical composition comprises a crystalline tazobactam
composition.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No. 61/883,530, filed Sep. 27, 2013, which is
incorporated herein in its entirety.
TECHNICAL FIELD
[0002] This disclosure relates to solid forms of ceftolozane.
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 from one solid form to another, which may
affect its suitability for pharmaceutical use. In addition,
different solid forms of a crystalline compound can incorporate
different types and/or different amounts of impurities. Different
solid forms of a compound can also have different chemical
stability upon exposure to heat and/or water over a period of
time.
[0004] Ceftolozane is a cephalosporin antibacterial agent, also
referred to as CXA-101, FR264205, or by chemical names such as
(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazo-
l-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carb-
oxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
-2-ene-2-carboxylate, and
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox-
yimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazol-
io}methyl-3-cephem-4-carboxylate. Ceftolozane sulfate is a
pharmaceutically acceptable ceftolozane salt of formula (I) that
can be formulated for intravenous administration or infusion.
##STR00001##
[0005] U.S. Pat. No. 7,129,232 discloses ceftolozane hydrogen
sulfate salt among other salts "with a base or an acid addition
salt such as a salt with an inorganic base, for example, an alkali
metal salt [e.g., sodium salt, potassium salt, etc.], an alkaline
earth metal salt [e.g., calcium salt, magnesium salt, etc.], an
ammonium salt; a salt with an organic base, for example, an organic
amine salt [e.g., trimethylamine salt, triethylamine salt, pyridine
salt, picoline salt, ethanolamine salt, triethanolamine salt,
dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.];
an inorganic acid addition salt [e.g., hydrochloride, hydrobromide,
sulfate, hydrogen sulfate, phosphate, etc.]; an organic carboxylic
or sulfonic acid addition salt [e.g., formate, acetate,
trifluoroacetate, maleate, tartrate, citrate, fumarate,
methanesulfonate, benzenesulfonate, toluenesulfonate, etc.]; and a
salt with a basic or acidic amino acid [e.g., arginine, aspartic
acid, glutamic acid, etc.]." In addition, U.S. Pat. No. 7,129,232
discloses a crystal solid form of ceftolozane sulfate obtained by
dissolving ceftolozane sulfate in a solution of water and ethanol,
adding seed crystals, to obtain the crystal form described herein
as (Comparative) Example 1. A synthesis of ceftolozane is also
described in U.S. Pat. No. 7,129,232.
[0006] As reported herein, there remains a need for solid forms of
ceftolozane having improved ceftolozane stability. For example, the
purity of ceftolozane in an aqueous ethanol solution during
precipitation according to the methods of U.S. Pat. No. 7,129,232
decreased from about 97% to about 68% during a 6-day stability test
(See Example 3), as measured by high performance liquid
chromatography (HPLC). Accordingly, there remains a need for solid
forms of ceftolozane greater ceftolozane stability for use in drug
substance and drug product development.
SUMMARY
[0007] Novel solid forms of ceftolozane (e.g., crystalline
ceftolozane sulfate) disclosed herein include ceftolozane sulfate
in Form 1 and Form 2, as well as compositions comprising a solid
form of ceftolozane comprising at least one or more of ceftolozane
sulfate Form 1 and ceftolozane sulfate Form 2. Novel compositions
also include ceftolozane sulfate solid Form 1, ceftolozane sulfate
solid Form 2 and/or crystalline and amorphous solid forms of
ceftolozane. A novel ceftolozane solid Form 1 and a novel
ceftolozane solid Form 2 of ceftolozane sulfate can both be
identified by X-ray Powder Diffraction (XRPD), both having one or
more characteristic diffractions at angles (2 theta.+-.0.2) of 24.2
and 37.8. In addition, ceftolozane diffractions in both solid Form
1 and solid Form 2 can produce the Raman spectra comprising one or
more of the following peaks (+/-5 cm.sup.-1) at about 597
cm.sup.-1, 716 cm.sup.-1, and 1329 cm.sup.-1. A preferred
ceftolozane composition can include ceftolozane in one or more
solid forms (e.g., solid Form 1 and/or solid Form 2) characterized
by an XRPD pattern with diffractions at angles (2 theta.+-.0.2) of
24.2 and 37.8, in addition to Raman spectra comprising one or more
of the following peaks at about 597 cm.sup.1, 716 cm.sup.1, and
1329 cm.sup.1.
[0008] A novel ceftolozane solid Form 1 of ceftolozane sulfate can
be identified by X-ray Powder Diffraction (XRPD), having one or
more characteristic diffractions at angles (2 theta.+-.0.2) of
12.4, 16.4, 22.6, 25.1, and 28.0. In addition, ceftolozane in solid
Form 1 can produce the Raman spectra comprising one or more of the
following peaks (+/-5 cm.sup.1) at 171 cm.sup.1, 743 cm.sup.1, 819
cm.sup.1, 1055 cm.sup.1, 2894 cm.sup.1, and 2976 cm.sup.-1.
[0009] A novel ceftolozane solid Form 2 of ceftolozane sulfate can
be identified by X-ray Powder Diffraction (XRPD), having one or
more characteristic diffractions at angles (2 theta.+-.0.2) of 4.4,
8.8, 11.0, 14.9, and 17.7. In addition, ceftolozane in solid Form 1
can produce the Raman spectra comprising one or more of the
following peaks (.+-.5 cm.sup.1) at 151 cm.sup.1, 684 cm.sup.1, 802
cm.sup.-1, 1174 cm.sup.-1, and 2953 cm.sup.-1.
[0010] The applicants have also discovered that novel ceftolozane
salt solid forms (e.g., Form 1 and Form 2 of ceftolozane sulfate)
can also be obtained by maintaining a ceftolozane salt solid form
under physical conditions effective to convert a ceftolozane salt
in a first solid form into a ceftolozane salt in a second solid
form. For example, performing a water sorption isotherm (e.g., FIG.
5) of ceftolozane sulfate in Form 1 showed a reversible
transformation between ceftolozane sulfate in solid Form 1 and
solid Form 2 as a function of relative humidity. The solid form of
ceftolozane can be changed by maintaining the ceftolozane at
certain relative humidity conditions (e.g., as described in the
water sorption isotherm for ceftolozane sulfate in FIG. 5).
Ceftolozane in solid Form 2 can be converted to ceftolozane in Form
1 by maintaining a sample at a relative humidity (RH) effective to
convert ceftolozane in Form 2 to ceftolozane into Form 1 at a
suitable temperature (e.g., RH of about 50% or higher at a
temperature of about 20-25 degrees C., preferably at least about
70% RH at a temperature of about 25 degrees C.). Once formed in
this manner, ceftolozane in solid Form 1 can be converted to
ceftolozane sulfate in Form 2 by reducing the RH (e.g., RH of about
20-40%). The ceftolozane sulfate in Form 2 can be converted to a
mixture of amorphous ceftolozane sulfate and Form 2 by reducing the
RH to less than about 20%.
[0011] The ceftolozane solid forms (Form 1 and Form 2) can be
obtained from a solution comprising isopropanol, or by maintaining
a ceftolozane solid form under conditions effective to convert a
first solid form into a second solid form (e.g., by maintaining
ceftolozane sulfate in Form 1 under physical conditions effective
to form ceftolozane sulfate in Form 2, or converting Form 2 under
physical conditions effective to form ceftolozane sulfate of Form
1). An improved manufacturing method can include the steps of (a)
combining ceftolozane sulfate with a molar excess of sulfuric acid
(e.g., about 2.5 molar equivalents of sulfuric acid to ceftolozane)
and isopropanol (e.g., about 20-40 volumes of isopropanol relative
to the amount of ceftolozane active) under conditions effective to
produce a ceftolozane solid form (e.g., ceftolozane sulfate Form
1), and (b) isolating the ceftolozane solid form (e.g., by
filtering the ceftolozane solid form from a solution comprising the
isopropanol).
[0012] The applicants have discovered novel methods of
manufacturing ceftolozane sulfate solid forms that provide improved
ceftolozane stability during manufacturing compared to the methods
of manufacturing ceftolozane solid forms disclosed in U.S. Pat. No.
7,129,232 (see Comparative Example 1 herein). The improved
manufacturing methods are based in part on the discovery that solid
forms of ceftolozane sulfate obtained by certain processes
comprising the use of isopropanol (e.g., as dscribed in Example 2a)
with ceftolozane provide improved ceftolozane stability in a liquid
phase during manufacturing (compared to the manufacturing methods
described in U.S. Pat. No. 7,129,232), as measured by a ceftolozane
purity of about 82% after a 6-day ceftolozane stability test of
Example 3 (compared to about 68% from ceftolozane solid forms
disclosed in U.S. Pat. No. 7,129,232). The novel ceftolozane solid
forms, including ceftolozane sulfate solid Form 1 and ceftolozane
solid Form 2, can be obtained from an aqueous solution with
isopropyl alcohol, even in the absence of ethanol. In contrast,
U.S. Pat. No. 7,129,232 discloses a ceftolozane solid form obtained
from an aqueous solution without isopropyl alcohol.
[0013] The manufacturing methods are useful for the manufacture of
antibiotic compositions comprising ceftolozane in one or more solid
forms suitable for treatment of infections. For example, a
pharmaceutical composition comprising ceftolozane for parenteral
administration can be obtained from ceftolozane sulfate in solid
Form 1 and/or solid Form 2 by a process comprising the steps of:
(a) forming a ceftolozane solution comprising ceftolozane sulfate
in a solid Form 1 and/or solid Form 2, and (b) lyophilizing the
ceftolozane solution to obtain a lyophilized ceftolozane
composition. The lyophilized ceftolozane composition can be
combined with tazobactam (or a pharmaceutically acceptable salt
thereof) to obtain a CXA-201 pharmaceutical composition suitable
for intravenous administration upon reconstitution.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 depicts two X-ray powder diffraction patterns of
novel solid forms ceftolozane sulfate. The upper pattern
corresponds to the product of Example 2a. The lower pattern
corresponds to the product of Example 2b.
[0015] FIG. 2 depicts two Raman spectra of novel solid forms of
ceftolozane sulfate. The upper pattern corresponds to the product
of Example 2a. The lower pattern corresponds to the product of
Example 2b.
[0016] FIG. 3 is a thermogravimetric analysis (TGA) curve for
ceftolozane sulfate in a solid form designated herein as Form
2.
[0017] FIG. 4 is a differential scanning calorimetry (DSC)
thermograms for ceftolozane sulfate in a solid form designated
herein as Form 2.
[0018] FIG. 5 is a moisture sorption/desorption isotherm for
ceftolozane sulfate solid forms.
DETAILED DESCRIPTION
[0019] Ceftolozane can be prepared as a pharmaceutically acceptable
salt in one or more solid forms. Ceftolozane is also known as
CXA-101; CAS registry number 689293-68-3;
(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazo-
l-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carb-
oxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
-2-ene-2-carboxylate, and
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox-
yimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazol-
io}methyl-3-cephem-4-carboxylate;
5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
3-[[4-[[[(2-aminoethyl)amino]carbonyl]amino]-2,3-dihydro-3-imino-2-methyl-
-1H-pyrazol-1-yl]methyl]-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1--
carboxy-1-methylethoxy)imino]acetyl]amino]-8-oxo-, (6R,7R)--; and
(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazo-
l-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carb-
oxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
-2-ene-2-carboxylate. Ceftolozane sulfate is an example of a
pharmaceutically acceptable salt of ceftolozane. The structure of
ceftolozane sulfate is shown below.
##STR00002##
Ceftolozane sulfate is also referred to as: CAS registry number
936111-69-2; 1H-Pyrazolium,
5-amino-4-[[[(2-aminoethyl)amino]carbonyl]amino]-2-[[(6R,7R)-7-[[(2Z)-2-(-
5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]a-
mino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-me-
thyl-, sulfate (1:1); and
5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-2-{[(6R,7R)-7-({(2Z)-2-(5-amin-
o-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)--
2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-methyl-1-
H-pyrazolium monosulfate.
[0020] Ceftolozane sulfate can occur in an amorphous solid form or
in a crystalline solid form or in mixtures of solid forms.
Crystalline solid forms of ceftolozane can exist in one or more
unique solid forms, which can additionally comprise one or more
equivalents of water or solvent (i.e., hydrates or solvates,
respectively).
[0021] As disclosed herein, crystalline ceftolozane sulfate
precipitated or crystallized from isopropanol/water has
significantly better stability in a solution comprising isopropanol
compared to the stability in a solution comprising ethanol, as used
to prepare crystalline ceftolozane sulfate precipitated from
ethanol/water, as previously described in U.S. Pat. No. 7,129,232
(see Example 3). Moreover, the crystalline forms precipitated or
crystallized from isopropanol/water have distinct characteristic
XRPD peaks (see Examples 1 and 2, and Tables 4 and 6) that are not
observed in previously disclosed crystal forms of ceftolozane
described in U.S. Pat. No. 7,129,232. Accordingly, provided herein
are novel crystalline ceftolozane sulfate solid forms,
pharmaceutical compositions thereof, and methods of preparing those
crystalline ceftolozane sulfate solid forms and methods of use
thereof.
[0022] Novel ceftolozane solid forms can be obtained from aqueous
solutions comprising ceftolozane and isopropyl alcohol (herein,
also called IPA, or isopropanol). As described in Example 2a,
ceftolozane sulfate in solid Form 1 can be obtained by forming a
ceftolozane solution comprising a ceftolozane salt, a strong acid
and IPA and maintaining the solution under conditions effective to
form a ceftolozane wet cake containing Form 1 of the ceftolozane
salt. Preferably, the ceftolozane solution is an aqueous solution
comprising ceftolozane and the strong acid (e.g., sulfuric acid) in
an amount providing least 1 molar equivalent of the strong acid to
the molar quantity of ceftolozane in the solution. In certain
examples, the Form 1 of ceftolozane is obtained from a ceftolozane
solution that is polish filtered and the temperature is adjusted
and maintained throughout the entire salt formation and isolation
process. An aqueous sulfuric acid (H.sub.2SO.sub.4) solution can be
charged to the batch. Optionally, this can be followed by seeding
with ceftolozane sulfate crystal. The batch is aged, followed by
the addition of IPA over a period of time. After the IPA addition,
the batch is agitated for an additional period, and then filtered.
The wet cake of ceftolozane sulfate is washed with a solution of
IPA and water
[0023] The ceftolozane solution is preferably maintained at a
temperature effective to provide a desired purity and yield of the
ceftolozane in solid Form 1, such as 8-12 degrees C. In addition to
the temperature (e.g., 8-12 degrees C., preferably about 10 degrees
C.), and amount of strong acid (e.g., sulfuric acid in an amount
providing 1-3 molar equivalents, and preferably 2.45-2.55 molar
equivalents, relative to the molar amount of ceftolozane), the
concentration of ceftolozane before salt formation (e.g., 75-85
g/L), seed amount (e.g., 0.1-1 w/w %) and aging time after seeding
(e.g., 2-4 hours) are also parameters that can be adjusted to
obtain ceftolozane in Form 1 solid form. Particularly preferred
processes for making Form 1 ceftolozane sulfate solid form include
maintaining an aqueous solution of ceftolozane sulfate, isopropyl
alcohol and sulfuric acid at a temperature of 8-12 degrees C. Table
1 provides the exemplary range of values for various process
parameters for the manufacturing of solid forms of ceftolozane
sulfate, along with preferred ranges and target (most preferred)
values for each process parameter.
TABLE-US-00001 TABLE 1 Process Parameters for the Formation and
Isolation of Ceftolozane Sulfate Solid Forms Exemplary Preferred
Process Parameter Range Range Target Value Ceftolozane
concentration 72 to 100 75 to 85 80 after final nanofiltration
(g/L) Sulfuric acid (equiv) 1.50 to 2.95 2.45 to 2.55 2.5 Seed
amount (w/w %) 0.03 to 4.0 0.1 to 1.0 0.3 Aging time, after seeding
(h) 1 to 5 2 to 4 3 IPA amount (vol) 20 to 40 29 to 31 30 IPA
addition time (h) 0.5 to 8 6 to 7 6.5 Aging time, after IPA 0 to 8
1 to 6 2 addition (h) Temperature (.degree. C.) 5 to 15 8 to 12 10
4:1 (v/v) IPA/water .gtoreq.2 .gtoreq.2 4 wash solution (vol)
[0024] Solid forms of ceftolozane can be obtained by methods
comprising the step of combining ceftolozane sulfate and a solvent,
such that a solution comprising ceftolozane sulfate is formed, and
such that crystalline ceftolozane sulfate precipitates from the
solution. Crystalline ceftolozane sulfate solid forms can be
obtained from methods that include the steps of: (1) combining
ceftolozane sulfate and a solvent, such that a solution of
ceftolozane sulfate is formed; and (2) combining an antisolvent
with the solution, wherein the antisolvent is miscible with the
solvent and wherein ceftolozane sulfate is partially or completely
insoluble in the antisolvent, such that crystalline ceftolozane
sulfate precipitates or crystallizes from the solution.
[0025] A ceftolozane sulfate composition can be obtained by a
process comprising the steps of: (a) forming a solution comprising
water, 72-100 g/L ceftolozane active and 1.5-2.95 molar equivalents
of sulfuric acid to ceftolozane; (b) combining the solution from
step (a) with 20-40 volumes of isopropyl alcohol added to the
solution over 0.5-8 hours to obtain solid ceftolozane sulfate; and
(c) isolating the solid ceftolozane sulfate from the solution. The
temperature of the solution can be about 0-20 degrees C.,
preferably 8-12 degress C. (e.g. 10 degrees C.). Optionally, the
process can further include adding a ceftolozane sulfate seed
crystal, preferably in an amount of 0.03-4.0% w/w and allowing the
seed crystal to age in the solution for about 1-5 hours.
Optionally, the process can include allowing the solution to age
for up to about 8 hours after adding the isopropyl alcohol.
[0026] In another aspect, methods of making crystalline ceftolozane
sulfate can include the steps of: (1) combining ceftolozane
freebase (i.e., the non-salt form of ceftolozane having a net
formal charge of zero) and a solvent, such that a solution of
ceftolozane freebase is formed; (2) combining an acid with the
solution of ceftolozane free base (e.g., in an amount providing a
molar equivalent or excess of the acid to the ceftolozane free
base, and/or an amount effective to adjust the pH of the
ceftolozane solution to about 1.5-2.0); and (3) allowing the
crystalline ceftolozane sulfate to precipitate or crystallize from
solution. In addition, the method can include adding an antisolvent
(preferably isopropyl alcohol) in an amount effective to provide a
desired rate or extent of precipitation and/or crystallization of
the ceftolozane in the solution. Accordingly, step (3) may further
comprise combining an antisolvent with the solution, wherein the
antisolvent is miscible with the solvent and wherein ceftolozane
sulfate is partially or completely insoluble in the antisolvent,
such that crystalline ceftolozane sulfate precipitates or
crystallizes from the solution. In some embodiments, the
temperature of the solution is adjusted to 0-20.degree. C. In other
embodiments, step (3) comprises the step of seeding the solution
with one or more crystals of ceftolozane sulfate. In some
embodiments, the volume of antisolvent that is added to the
solution is 20-40 volumes relative to the ceftolozane. In some
embodiments, the temperature of the solution formed in step (1) is
adjusted to 0-20.degree. C. before proceeding to step (2). In one
embodiment, the method of making crystalline ceftolozane sulfate
can also include the step of: (4) drying the precipitated or
crystallized crystalline ceftolozane sulfate. Drying may comprise
techniques including, but not limited to, air-drying, exposure to
vacuum, exposure to a neutral gas (e.g., nitrogen) flow and
heating.
[0027] In an alternative embodiment, the acid (e.g., sulfuric acid)
may first be combined with the solvent, and the resulting mixture
then combined with ceftolozane. Alternatively, ceftolozane and the
acid (e.g., sulfuric acid) may first be combined, and the resulting
mixture then combined with the solvent. In one embodiment, the
antisolvent is added to the solution of ceftolozane sulfate or
freebase. In another embodiment, the solution of ceftolozane
sulfate or freebase is added to the antisolvent. In certain
embodiments, the solvent is selected from the group consisting of
water and sulfuric 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, isopropanol, tert-butylmethyl ether, tetrahydrofuran,
toluene and mixtures thereof. In a preferred embodiment, the
solvent is water. In another preferred embodiment, the antisolvent
is isopropanol.
[0028] Also provided herein is a method of making crystalline
ceftolozane sulfate, comprising one or more steps selected from the
group consisting of: (1) combining ceftolozane freebase, sulfuric
acid and water, such that an aqueous solution of ceftolozane
sulfate is formed; and (2) combining isopropanol with the aqueous
solution, such that crystalline ceftolozane sulfate precipitates or
crystallizes from the solution. In another aspect, provided herein
is a method of making crystalline ceftolozane sulfate, comprising:
(1) combining ceftolozane freebase, sulfuric acid, and a
solvent/antisolvent mixture, such that a solution of ceftolozane
sulfate is formed; and (2) combining an antisolvent with the
solution, wherein the antisolvent is miscible with the solvent and
wherein ceftolozane sulfate is partially or completely insoluble in
the antisolvent, such that crystalline ceftolozane sulfate
precipitates or crystallizes from the solution. In another aspect,
provided herein is a method of making crystalline ceftolozane
sulfate comprising the steps of: a) dissolving ceftolozane sulfate
in water to obtain a first solution of ceftolozane sulfate; b)
combining the first solution of ceftolozane sulfate with
isopropanol to afford a second solution of ceftolozane sulfate; c)
crystallizing ceftolozane sulfate from the second solution to
obtain crystalline ceftolozane sulfate. In another aspect, provided
herein is crystalline ceftolozane sulfate produced according to any
one of the preceding methods. In another aspect, provided herein is
crystalline ceftolozane sulfate obtainable by any one of the
preceding methods. The processes and methods described herein may
also further comprise adding one or more seed crystals of
crystalline ceftolozane sulfate.
[0029] As used herein, the term "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/isopropanol.
[0030] The solid forms of ceftolozane can be identified by various
analytical techniques, such as X-ray powder diffraction (XRPD).
Solid forms of ceftolozane sulfate in solid Form 1 and a novel
ceftolozane solid Form 2 of ceftolozane sulfate can both be
identified by XRPD both having one or more shared characteristic
diffractions at angles (2 theta.+-.0.2) of 24.2 and 37.8. In
addition, ceftolozane in both solid Form 1 and solid Form 2 can
both produce the Raman spectra comprising one or more of the
following peaks (+/-5 cm.sup.-1) at about 597 cm.sup.-1, 716
cm.sup.-1, and 1329 cm.sup.1. A preferred ceftolozane composition
can include ceftolozane in one or more solid forms (e.g., solid
Form 1 and/or solid Form 2) characterized by XRPD pattern with
diffractions at angles (2 theta.+-.0.2) of 24.2 and 37.8, in
addition to Raman spectra comprising one or more of the following
peaks (+/-5 cm.sup.1) at about 597 cm.sup.1, 716 cm.sup.1, and 1329
cm.sup.1. In addition, compositions comprising ceftolozane sulfate
in solid Form 1 and/or solid Form 2 can be identified by XRPD
patterns with diffractions at 2-theta values (2 theta.+-.0.2)
indicated in Table 4 (for Form 1) and/or Table 6 (for Form 2),
respectively.
[0031] A novel ceftolozane solid Form 1 of ceftolozane sulfate can
be identified by X-ray Powder Diffraction (XRPD), having one or
more characteristic diffractions at angles (2 theta.+-.0.2) of
12.4, 16.4, 22.6, 25.1, and 28.0. In addition, ceftolozane in solid
Form 1 can produce the Raman spectra comprising one or more of the
following peaks (+/-5 cm.sup.1) at 171 cm.sup.1, 743 cm.sup.1, 819
cm.sup.1, 1055 cm.sup.1, 2894 cm.sup.1, and 2976 cm.sup.-1. In one
embodiment, provided herein is crystalline ceftolozane sulfate
Forml characterized by an X-ray powder diffraction pattern having
peaks at substantially the same angles as the upper spectrum in
FIG. 1. In another embodiment, the crystalline ceftolozane sulfate
Form 1 is characterized by an X-ray powder diffraction pattern
having one or more peaks at substantially the angles (2
theta.+-.0.2) as Table 4.
[0032] A novel ceftolozane solid Form 2 of ceftolozane sulfate can
be identified by X-ray Powder Diffraction (XRPD), having one or
more characteristic diffractions at angles (2 theta.+-.0.2) of 4.4,
8.8, 11.0, 14.9, and 17.7. In addition, ceftolozane in solid Form 1
can produce the Raman spectra comprising one or more of the
following peaks (.+-.5 cm.sup.-1) at 151 cm.sup.-1, 684 cm.sup.-1,
802 cm.sup.1, 1174 cm.sup.1, and 2953 cm.sup.-1. In one embodiment,
the crystalline ceftolozane sulfate Form 2 is characterized by an
X-ray powder diffraction pattern having characteristic peaks at
substantially the same angles as the lower spectrum in FIG. 1. In
another embodiment, the crystalline ceftolozane sulfate Form 2 is
characterized by an X-ray powder diffraction pattern having one or
more peaks at substantially the same angles (2 theta.+-.0.2) as
Table 6.
[0033] Crystalline forms of ceftolozane sulfate can also be
characterized by their water content. In one embodiment, the
crystalline ceftolozane sulfate comprises 11-27%, 12-26%, 13-25%,
14-24%, 15-23%, 16-22%, or 17-21% of water by weight. In a
particular embodiment, the crystalline ceftolozane sulfate
comprises 18-20% of water by weight. In another embodiment, the
crystalline ceftolozane sulfate comprises about 26.3% by weight of
water. In a particular embodiment, the crystalline ceftolozane
sulfate is ceftolozane sulfate decahydrate.
[0034] Crystalline forms of ceftolozane sulfate can also be defined
by their water content. In one embodiment, crystalline ceftolozane
sulfate comprises 4-10%, 5-9%, or 6-8% of water by weight. Form 1
of ceftolozane sulfate can include about 18-20% water. Form 2 of
ceftolozane sulfate can include less than about 11% water, and
preferably about 5-11% water, and most preferably about 7-8%
water.
[0035] In another embodiment, the crystalline ceftolozane sulfate
comprises about 7% of water by weight. In a particular embodiment,
the crystalline ceftolozane sulfate is ceftolozane sulfate
trihydrate.
[0036] In some embodiments, crystalline ceftolozane sulfate can be
characterized by Raman spectroscopy. In a particular embodiment,
the crystalline ceftolozane sulfate in Form 1 has a Raman spectrum
substantially in accordance with the upper spectrum shown in FIG.
2. In another particular embodiment, the crystalline ceftolozane
sulfate in Form 1 has a Raman spectrum with one or more peaks at
substantially the same positions (.+-.5 cm.sup.1) as shown in Table
5. Ceftolozane solid Form 1 can produce Raman shift peaks
comprising one or more of the certain peaks not observed in Form 1,
at about (.+-.5 cm.sup.-1) 171 cm.sup.-1, 743 cm.sup.-1, 819
cm.sup.-1, 1055 cm.sup.-1, 2894 cm.sup.1, and 2976 cm.sup.1.
[0037] In other embodiments, the crystalline ceftolozane sulfate in
Form 2 has a Raman spectrum substantially in accordance with the
lower spectrum shown in FIG. 2. In another particular embodiment,
the crystalline ceftolozane sulfate in Form 2 has a Raman spectrum
with one or more peaks at substantially the same positions (.+-.5
cm.sup.1) as shown in Table 7. Ceftolozane solid Form 2 can produce
Raman shift peaks comprising one or more of the peaks at about
(.+-.5 cm.sup.1) 151 cm.sup.1, 684 cm.sup.1, 802 cm.sup.1, 1174
cm.sup.1, and 2953 cm.sup.1.
[0038] Ceftolozane in solid Form 1 and solid Form 2 are both
characterized by intense Raman shift peaks (+/-5 cm.sup.1) at about
597 cm.sup.1, 716 cm.sup.1, and 1329 cm.sup.1. In addition,
ceftolozane solid Form 1 and Form 2 can produce Raman shift peaks
comprising one or more of the following peaks at indicated in both
Table 5 and 7 (.+-.5 cm.sup.1).
[0039] In another aspect, provided herein is a composition
comprising amorphous and crystalline solid forms of ceftolozane
sulfate. In one embodiment, the composition comprises crystalline
ceftolozane sulfate and amorphous ceftolozane sulfate, wherein the
amorphous ceftolozane sulfate is present in an amount selected from
the following ranges: 90-99%, 80-89%, 70-79%, 60-69%, 50-59%,
40-49%, 30-39%, 20-29%, 10-19%, 1-9% and 0-0.99%.
[0040] In some embodiments, the crystalline ceftolozane sulfate is
a hydrate. In one embodiment, the crystalline ceftolozane sulfate
is ceftolozane sulfate decahydrate. In a particular embodiment, the
crystalline ceftolozane sulfate comprises
5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-2-{[(6R,7R)-7-({(2Z)-2-(5-amin-
o-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)--
2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-methyl-1-
H-pyrazolium monosulfate and water in a 1:10 molar ratio.
[0041] In another embodiment, the crystalline ceftolozane sulfate
is ceftolozane sulfate trihydrate. In a particular embodiment, the
ceftolozane sulfate comprises
5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-2-{[(6R,7R)-7-({(2Z)-2-(5-amin-
o-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)--
2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-methyl-1-
H-pyrazolium monosulfate and water in a 1:3 molar ratio.
[0042] Compared with previous crystalline forms of ceftolozane
sulfate, certain novel crystalline forms of ceftolozane sulfate
have advantageous properties. For example, these crystalline forms
were found to be more chemically stable, which can be beneficial to
the preparation of various drug formulations.
[0043] A pharmaceutical composition can comprise, and/or be
obtained from, the solid form of ceftolozane sulfate designated as
ceftolozane sulfate Form 2 that produces an X-ray powder
diffraction (XRPD) pattern having diffractions at angles (2
theta.+-.0.2) of 4.4, 8.8, 11.0, 14.9 and 17.7. The ceftolozane
sulfate can produce Raman shift peaks (+/-5 cm.sup.-1) at about 151
cm.sup.-1, 684 cm.sup.1, 802 cm.sup.1, 1174 cm.sup.1 and 2953
cm.sup.1.
[0044] A pharmaceutical composition can contain or be obtained from
a solid form of ceftolozane characterized by one or more of the
following: (a) the solid form of ceftolozane sulfate produces an
XRPD pattern further comprising diffractions at angles (2
theta.+-.0.2): 4.4, 8.8, 11.0, 14.9, and 17.7; (b) the solid form
of ceftolozane sulfate of claim 1 that produces an XRPD pattern
further comprising one or more additional diffractions at angles (2
theta.+-.0.2) listed in Table 6; (c) the solid form of ceftolozane
sulfate that produces Raman shift peaks at about (.+-.5 cm.sup.1)
151 cm.sup.1, 684 cm.sup.1, 802 cm.sup.1, 1174 cm.sup.1, and 2953
cm.sup.1; (d) the solid form of ceftolozane sulfate of claim 1 that
produces one or more additional Raman shift peaks at values listed
in Table 7; and any combination of one or more of characteristics
(a)-(d).
[0045] A pharmaceutical composition can contain or be obtained from
a lyophilized ceftolozane composition obtained by a process
comprising the steps of: (a) combining ceftolozane sulfate in the
solid form designated herein as ceftolozane sulfate in solid Form
2, with water, sodium chloride and L-arginine to form an aqueous
solution; and (b) lyophilizing the aqueous solution to form the
lyophilized composition comprising ceftolozane sulfate. The
pharmaceutical composition obtained by such a method can include
performing a lyophilization cycle characterized by one or more of
the following characteristics: (a) not more than 150 mg ceftolozane
free base/g bulk solution concentration, (b) no more than 3 cm fill
depth, (c) freezing to at least -40.degree. C. during the
lyophilization cycle, (d) drying to no more than 40.degree. C., and
(e) single- or multi-step drying and setting chamber pressure
during the start of primary drying at not more than 400
.mu.bar.
[0046] A ceftolozane sulfate composition can be obtained by a
process comprising the steps of: (a) forming a solution comprising
water, 72-100 g/L ceftolozane active and 1.5-2.95 molar equivalents
of sulfuric acid to ceftolozane; (b) combining the solution from
step (a) with 20-40 volumes of isopropyl alcohol added to the
solution over 0.5-8 hours to obtain solid ceftolozane sulfate; and
(c) isolating the solid ceftolozane sulfate composition from the
solution.
[0047] Pharmaceutical compositions comprising ceftolozane and
tazobactam can be obtained by blending a first composition
comprising a therapeutically effective amount of ceftolozane with a
second composition comprising a therapeutically effective amount of
tazobactam to form a blended pharmaceutical composition. The
pharmaceutical composition can comprise ceftolozane or a
therapeutically effective salt thereof and tazobactam or a
pharmaceutically effective salt thereof in an amount providing
about 500 mg of tazobactam active per 1,000 mg of ceftolozane
active. The pharmaceutical antibiotic composition preferably
includes ceftolozane and tazobactam in a 2:1 weight ratio of
ceftolozane active to tazobactam active ("CXA-201"), which displays
antibacterial activity, including antibiotic activity against
infections caused by many Gram-negative pathogens such as
Pseudomonas aeruginosa (P. aeruginosa). In particular, CXA-201 is a
pharmaceutical composition useful for intravenous administration
for the treatment of complicated intra-abdominal infections and/or
complicated urinary tract infections, and is being evaluated for
treatment of pneumonia.
[0048] Methods of treating an infection selected from the group
consisting of: complicated intra-abdominal infection (cIAI),
complicated urinary tract infection (cUTI), or hospital
acquired/ventilator-associated bacterial pneumonia (HABP/VABP) are
also provided herein. These methods can include administering to a
patient an injectable pharmaceutical composition comprising
ceftolozane in an injectable preparation prepared from a
lyophilized composition obtained by a process comprising the steps
of: (a) combining the ceftolozane sulfate in a solid form that
produces an X-ray powder diffraction (XRPD) pattern having
diffractions at angles (2 theta.+-.0.2) of 4.4, 8.8. 11.0, 14.9,
and 17.7 with water to form an aqueous solution; and (b)
lyophilizing the aqueous solution to form the lyophilized
ceftolozane composition comprising ceftolozane sulfate.
[0049] Pharmaceutical compositions can be obtained by combining
tazobactam (or a pharmaceutically acceptable salt thereof) in one
or more solid forms with a ceftolozane composition comprising
ceftolozane in one or more salts and/or solid forms. The
ceftolozane in the pharmaceutical composition can be ceftolozane
sulfate in one or more solid forms disclosed herein, including
amorphous, Form 1, Form 2 and/or combinations thereof. The
ceftolozane in the pharmaceutical composition can be obtained by a
process comprising lyophilizing a solution of ceftolozane sulfate
in solid Form 1, solid Form 2 and/or combinations thereof. For
example, the ceftolozane in the pharmaceutical composition can be
prepared in the absence of tazobactam by forming an aqueous
solution comprising ceftolozane sulfate in solid Form 1, solid Form
2 and/or combinations thereof and other components including
excipients, stabilizers, pH adjusting additives (e.g., buffers) and
the like. Non-limiting examples of these additives include sodium
chloride, citric acid and L-arginine. For example, the use of
sodium chloride results in greater stability; L-arginine is used to
adjust the aqueous solution to a pH of 5-7 (e.g., to pH 6-7) and to
increase the solubility of ceftolozane; and citric acid is used to
prevent discoloration of the product, due to its ability to chelate
metal ions. In one embodiment, the pH of the first aqueous solution
is suitable for making an injectable product (e.g., a pH range of
5-7, including 6-7). Preferably, the first aqueous solution
comprises about 125 mg-500 mg of a ceftolozane stabilizing agent
(such as sodium chloride) per 1,000 mg of ceftolozane active. The
ceftolozane can be included as an amount of ceftolozane sulfate of
formula (I) containing at least about 1,000 mg ceftolozane active.
The aqueous solution comprising ceftolozane (e.g., ceftolozane
sulfate in Form 2, and/or other solid forms disclosed herein) is
then lyophilized to form a first lyophilized ceftolozane
composition, which is combined with tazobactam, e.g., the
lyophilized tazobactam (e.g., lyophilized tazobactam sodium) or
crystalline tazobactam
[0050] The pharmaceutical composition can be obtained by combining
the ceftolozane composition with a (second) tazobactam composition
(e.g., preferably, but not necessarily, prepared in the absence of
ceftolozane) by forming a second solution comprising tazobactam.
The tazobactam can be included in an amount providing about 500 mg
of tazobactam active per 1,000 mg ceftolozane active (i.e., a 1:2
weight ratio of tazobactam active to ceftolozane active).
Tazobactam is a beta-lactamase inhibitor in its free acid form.
Unless otherwise indicated, tazobactam can be a free acid, a sodium
salt, an arginine salt, or a hydrate or solvate thereof. In one
embodiment, the tazobactam in the (second) tazobactam composition
is tazobactam acid and the second composition further comprises
sodium bicarbonate or sodium hydroxide. Lyophilizing tazobactam in
the presence of sodium bicarbonate or sodium hydroxide forms a
lyophilized tazobactam sodium, which can then be further blended
with the (first) lyophilized ceftolozane composition.
[0051] Pharmaceutical compositions can be obtained by
lyophilization (e.g., lyophilizing an aqueous ceftolozane solution
obtained by dissolving ceftolozane in Form 2 and/or Form 1 with
other components such as a stabilizing agent, a chelating agent
and/or an alkalizing agent). 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).
[0052] Pharmaceutical compositions comprising ceftolozane and
tazobactam can be formulated to treat infections by parenteral
administration (including subcutaneous, intramuscular, and
intravenous) administration. Pharmaceutical compositions may
additionally comprise excipients, stabilizers, pH adjusting
additives (e.g., buffers) and the like. Non-limiting examples of
these additives include sodium chloride, citric acid and
L-arginine. For example, the use of sodium chloride results in
greater stability; L-arginine is used to adjust pH and to increase
the solubility of ceftolozane; and citric acid is used to prevent
discoloration of the product, due to its ability to chelate metal
ions. In one particular embodiment, the pharmaceutical compositions
described herein are formulated for administration by intravenous
injection or infusion.
[0053] The pharmaceutical antibiotic compositions can be provided
in a unit dosage form container (e.g., in a vial or bag, or the
like). The unit dosage form can be dissolved with a
pharmaceutically acceptable carrier, and then intravenously
administered. The unit dosage form comprises 1000 mg of ceftolozane
active and 500 mg tazobactam, typically 1000 mg ceftolozane active
as ceftolozane sulfate and 500 mg of tazobactam active as
tazobactam sodium, argininate or free acid. The unit dosage forms
are commonly stored in vials.
[0054] In one aspect, provided herein is a unit dosage form
container (e.g., a bag, vial or the like) containing a unit dosage
form of a pharmaceutical composition formulated for parenteral
administration for the treatment of complicated intra-abdominal
infections, the pharmaceutical composition comprising a
therapeutically effective amount of ceftolozane sulfate and
tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of
tazobactam active, the pharmaceutical composition obtained by a
process comprising the steps of:
[0055] a. lyophilizing a first aqueous solution in the absence of
tazobactam, the first aqueous solution comprising ceftolozane
sulfate, 125 mg to 500 mg of sodium chloride per 1,000 mg of
ceftolozane active, L-arginine and/or citric acid in an amount
effective to adjust the pH of the first aqueous solution to 5-7
(e.g., 6-7) prior to lyophilization to obtain a first lyophilized
ceftolozane composition,
[0056] b. lyophilizing a second solution in the absence of
ceftolozane, the second solution comprising tazobactam being
lyophilized to form a second lyophilized tazobactam composition;
and
[0057] c. blending the first lyophilized ceftolozane composition
and the second lyophilized tazobactam composition to obtain a
blended pharmaceutical composition in the unit dosage form.
[0058] In one embodiment of the unit dosage form container, the
tazobactam in the second solution is tazobactam acid, and wherein
the tazobactam acid in the second solution is lyophilized in the
presence of sodium bicarbonate or sodium hydroxide, thereby forming
lyophilized tazobactam sodium in the second lyophilized tazobactam
composition.
[0059] The pharmaceutical compositions provided herein comprising
ceftolozane sulfate and tazobactam in a ratio of 1,000 mg
ceftolozane active per 500 mg of tazobactam active, can be obtained
by a process comprising the steps of:
[0060] a. lyophilizing a first aqueous solution in the absence of
tazobactam, the first aqueous solution comprising ceftolozane
sulfate at a pH of 5-7 (e.g, 6-7) prior to lyophilization to obtain
a first lyophilized ceftolozane composition,
[0061] b. blending the first lyophilized ceftolozane composition
with tazobactam to obtain an antibacterial composition.
[0062] As provided herein, ceftolozane can be stabilized in a
pharmaceutical composition comprising ceftolozane and a stabilizing
effective amount of a stabilizing agent selected from the group
consisting of: sodium chloride, dextran 40, lactose, maltose,
trehalose and sucrose. The pharmaceutical compositions provided
herein are based in part on the surprising discovery that
ceftolozane pharmaceutical compositions comprising these
stabilizing agents demonstrate improved ceftolozane residual rates
(e.g., % ceftolozane remaining after 3 days at 70 degrees C. as
measured by HPLC) and/or chemical stability (e.g., lower reduction
in ceftolozane purity measured by HPLC after 7 days at 60 degrees
C. in a stability test) compared control samples comprising
ceftolozane without a stabilizing agent.
[0063] Accordingly, preferred pharmaceutical antibiotic
compositions can include ceftolozane sulfate and a stabilizing
agent (e.g., 300 to 500 mg of a stabilizing agent per 1,000 mg
ceftolozane active) in a lyophilized unit dosage form (e.g., powder
in a container). The unit dosage form can be dissolved with a
pharmaceutically acceptable carrier (e.g., 0.9% sodium chloride
aqueous isotonic saline and/or water for injection), and then
intravenously administered. In certain ceftolozane compositions,
the stabilizing agent can be selected from the group consisting of:
sodium chloride, lactose, maltose and dextran 40, and/or selected
from the group consisting of: sodium chloride, trehalose and
sucrose.
[0064] Ceftolozane pharmaceutical compositions comprising 125 to
500 mg (e.g., 480 to 500 mg) of sodium chloride per 1000 mg of
ceftolozane active demonstrate improved ceftolozane purity and
chemical stability compared to pharmaceutical compositions
comprising ceftolozane with comparatively less sodium chloride. The
disclosed ceftolozane pharmaceutical compositions comprise a
stabilizing amount of sodium chloride (e.g., 125 to 500 mg of
sodium chloride [more specifically, 480 to 500 mg] per 1000 mg of
ceftolozane active). Certain preferred compositions demonstrate
improved ceftolozane purity and chemical stability compared with
pharmaceutical compositions comprising ceftolozane with
comparatively less sodium chloride. For example, the disclosed
pharmaceutical compositions typically comprise less than about 4%
total impurity after being stored for seven days at 60 degrees C.,
as determined by HPLC. Alternatively, the disclosed pharmaceutical
compositions comprise less than about 2% of the impurity
represented by Peak 1 after being stored for seven days at
60.degree. C., as determined by HPLC (refer to the HPLC method
described in Table 10), where Peak 1 has a retention time relative
to ceftolozane of approximately 0.15.
[0065] Another embodiment of the invention is a container
containing a unit dosage form of a pharmaceutical composition
formulated for parenteral administration for the treatment of
complicated intra-abdominal infections or complicated urinary tract
infections. The container can be obtained by a process comprising
the steps of: a) lyophilizing an aqueous solution comprising 189 mg
sodium from sodium chloride per 1000 mg ceftolozane active in the
form of ceftolozane sulfate and further comprising citric acid, and
L-arginine to obtain a lyophilized ceftolozane composition; and b)
filling a sufficient quantity of the lyophilized composition into a
container to obtain a unit dosage form comprising a ceftolozane
stabilizing effective amount of sodium from sodium chloride (e.g.,
125-500 mg sodium chloride per 1 g ceftolozane active) and 1,000 mg
of ceftolozane active in the form of ceftolozane sulfate. In one
aspect, the pH of the aqueous solution is 6.0 to 7.0. In another
aspect the pharmaceutical composition is formulated for parenteral
administration by reconstituting the pharmaceutical composition in
the container (e.g., with 10 mL of diluent such as water for
injection or isotonic saline) followed by addition of the
reconstituted pharmaceutical composition to a carrier for injection
(e.g., about 100 mL of isotonic saline or other pharmaceutically
acceptable carrier for intravenous administration). Optionally, the
container is also filled with tazobactam (e.g., a lyophilized
tazobactam such as tazobactam sodium). In yet another aspect, the
pharmaceutical composition is a liquid composition comprising 487
mg sodium chloride per 1,000 mg of ceftolozane active and
tazobactam in an amount providing about 500 mg tazobactam acid
equivalent per 1,000 mg of ceftolozane active, formulated for
parenteral administration and the pH of the aqueous solution is 5.0
to 7.0 and preferably about 6.0 to 7.0.
[0066] The pharmaceutical composition in the container can also be
a Ceftolozane/Tazobactam for Injection Drug Product, 1000 mg/500
mg. It is presented as a combination of two sterile active powders
in a single container intended for reconstitution and intravenous
infusion. In one embodiment, the drug product is prepared by
converting ceftolozane sulfate to a sterile composition as a powder
with excipients citric acid, sodium chloride and L-arginine. This
is can done by lyophilization, as described herein. Tazobactam
sodium drug substance can be presented as a sterile powder without
any excipients. The tazobactam sodium drug substance can be
lyophilized, spray dried or provided as a crystalline material. The
drug product is then prepared by aseptically filling the two
powders (e.g., the two separately lyophilized drug powders)
sequentially into a single container.
[0067] In an embodiment, the container of ceftolozane/tazobactam
for injection contains approximately 2255 mg ceftolozane sterile
composition powder that contains 1147 mg ceftolozane sulfate, which
is equivalent to 1000 mg ceftolozane free base, as well as
approximately 537 mg tazobactam sodium sterile drug substance,
equivalent to 500 mg tazobactam free acid. At the time of
administration, the container is reconstituted with 10 mL vehicle,
sterile 5% Dextrose Injection USP, Water for Injection or 0.9%
Sodium Chloride Injection USP, then the container contents further
diluted in an infusion bag of 0.9% Sodium Chloride Injection USP or
5% Dextrose Injection USP, for administration.
[0068] Ceftolozane-containing pharmaceutically compositions can
also include an amount of tazobactam in a pharmaceutically
acceptable form providing 500 mg of tazobactam acid per 1,000 mg of
ceftolozane active as a composition formulated for injection, or
for reconstitution prior to parenteral administration. In one
product presentation, ceftolozane/tazobactam can be provided in a
single container comprising ceftolozane sulfate and tazobactam
sodium, administered by reconstituting a container-unit dosage form
container of solid ceftolozane/tazobactam to form a reconstituted
injectable formulation. In one presentation (e.g., for treatment of
certain urinary tract infections and/or certain intra-abdominal
infections), each unit dosage form container of CXA-201 can contain
1000 mg of ceftolozane active (free base equivalent weight, e.g.,
provided as a pharmaceutically acceptable salt such as ceftolozane
sulfate) and sterile tazobactam sodium at a quantity equivalent of
500 mg of tazobactam free acid, in a solid form. In another
presentation (e.g., for treatment of hospital
acquired/ventilator-associated bacterial pneumonia (HABP/VABP)), a
ceftolozane/tazobactam product can include a unit dosage form
container providing 2,000 mg of ceftolozane active (e.g., as an
equivalent amount of ceftolozane sulfate) and 1,000 mg of
tazobactam acid (e.g., as an equivalent amount of tazobactam
sodium). Ceftolozane/tazobactam compositions display potent
antibacterial activity against various gram-negative infections
such as, for example, complicated intra-abdominal infection (cIAI),
complicated urinary tract infection (cUTI), or hospital
acquired/ventilator-associated bacterial pneumonia (HABP/VABP).
[0069] Ceftolozane/tazobactam can be used for treating an infection
selected from the group consisting of: urinary tract infections,
and intra-abdominal infections. The methods of treatment can
include intravenously administering to a patient in need thereof a
therapeutically effective amount of a pharmaceutical composition
comprising ceftolozane sulfate and an amount of tazobactam
providing about 500 mg of tazobactam active per 1,000 mg of
ceftolozane active, the ceftolozane sulfate in the pharmaceutical
composition obtained from a ceftolozane sulfate solid form obtained
by a process comprising the steps of: (a) combining the ceftolozane
sulfate in a solid form, designated as ceftolozane sulfate Form 2,
with water, sodium chloride and L-arginine to form an aqueous
solution; (b) lyophilizing the aqueous solution to form the
lyophilized ceftolozane composition comprising ceftolozane sulfate;
(c) combining the lyophilized ceftolozane composition with
tazobactam to obtain the pharmaceutical composition; (d)
reconstituting the pharmaceutical composition in a pharmaceutically
acceptable diluent; and (e) intravenously administering the
reconstituted pharmaceutical composition to the patient.
EXAMPLES
Instrumentation and Methods
[0070] Other than Comparative Example 1, and unless otherwise
indicated, the following instrumentation and methods were used in
the working Examples described herein. Comparative Example 1 is
reported in U.S. Pat. No. 7,232,129.
X-Ray Powder Diffraction (XRPD)
[0071] High Resolution X-ray Powder Diffraction experiments
(Bruker, AXS D8 Advance) were performed on a Bruker D8
diffractometer using Cu K.alpha. radiation (40 kV, 40 mA), 0-20
goniometer, and primary & secondary soller slits (2.5.degree.),
a Ge monochromator and Lynxeye detector (opening angle of
2.948.degree.). Certified Corundum standard (NIST 1976) was used to
check the performance of the instrument. Data collection was
performed by the Diffrac.Suite Measurement Center v2.2.47.1 and the
data was analyzed and presented using Diffrac.EVA v2.0 or v3.0.
[0072] Samples were tested under ambient conditions. Approximately
500 mg of each sample was grinded for 3 minutes in a mortar and
pestle. The sample was prepared by back-loading the triturated
material into the sample holder and supporting it with a zero
background silicon wafer. Once tightly packed, a flat surface was
formed. When the sample was carefully flipped over, the appearance
of the API in the sample holder appeared very similar to the
appearance of the Corundum sample for NIST used to verify the
performance of the instrument. The scan type of coupled
TwoTheta/Theta was used for the data collection. The angular range
was 2 to 50.degree. 2.theta., and the step size was 0.001.degree.
2.theta.. Collection Time was 1s for the each step. The geniometer
radius was set at 280 mm. Sample rotation speed was 15 rpm, and the
slit size was 0.1 mm.
Thermal Analysis
[0073] Thermo Gravimetric Analysis (TGA) experiments were performed
on a TA Instruments Discovery Series TGA. The calibration for
temperature was carried out using certified indium. Typically, 3-15
mg of a sample was flattened into sealed aluminum pans. Data was
acquired for samples with and without a pinhole. For samples with a
pinhole, once crimped and sealed, the auto-sampler punched the lid
of the sample with its internal puncher right before analysis of
the sample. Samples were heated at 20.degree. C./min from
30.degree. C. to 400.degree. C. Dry nitrogen was purged into the
system during the experiment at a rate of 50 ml/min. The software
used to control the instrument was TRIOS Explorer Software
v5.3.0.75. TRIOS software v2.40.1838 or v2.04.04563 was used for
data analysis.
[0074] Differential Scanning calorimetry (DSC) experiments were
performed on a TA Instruments Q2000 was used for collecting DSC
data. The calibration for thermal capacity was carried out using
sapphire and the calibration for energy and temperature was carried
out using certified indium. Typically, 3-10 mg of a sample is
flattened into sealed aluminum hermetic pans and the weight
accurately recorded. Data was acquired for samples with a pinhole
in the lid. Samples were heated at 10.degree. C./min from
25.degree. C. to 350.degree. C. Dry nitrogen was purged into the
system during the experiment at a rate of 50 ml/min. The software
used to control the instrument is the Advantage for Q Series
v2.9.0.396 and the Thermal Advantage v5.4.0. Data was analyzed
using the Universal Analysis v4.5A software.
Gravimetric Dynamic Vapour Sorption
[0075] Gravimetric dynamic vapor sorption data (FIG. 5) was
obtained using a SMS DVS Intrinsic moisture sorption analyser,
controlled by DVS Intrinsic Control software v1.0.0.30. The sample
temperature was maintained at 25.degree. C. by the instrument
controls. The humidity was controlled by mixing streams of dry and
wet nitrogen. The relative humidity was measured by a calibrated
Rotronic probe, located near the sample. The weight change of the
sample as a function of % RH was constantly monitored by the
microbalance (accuracy .+-.0.005 mg). Approximately 40 mg of sample
was placed in a tared mesh stainless basket under ambient
conditions. Weight reference was established at the start of an
experiment. Moisture sorption isotherm parameters were described as
below:
TABLE-US-00002 TABLE 2 Parameters Values Scan 1 Adsorption 40%-90%
Scan 2 Desorption/Adsorption 90%-0%/0%-40% Interval (RH step
increments) 10% Number of Scans 4 (double cycle) Flow rate for dry
and wet N.sub.2 200 ml/min Temperature 25.degree. C. Temperature
Stability 0.2.degree. C./min Time out 6 hrs
Data analysis was undertaken in Microsoft Excel using DVS Analysis
Suite v6.0. The sample was recovered after completion of the
isotherm experiment for solid state characterization.
Spectroscopy Measurement
[0076] Raman spectra were acquired on a Fourier transform Raman 960
spectrometer (Thermo Nicolet) equipped with a germanium (Ge)
detector. Wavelength verification was performed using sulfur and
cyclohexane. Each sample was packed into a pellet and placed into a
pellet holder accessory for analysis. Approximately 0.505 W of
Nd:YVO.sub.4 laser power (1064 nm excitation wavelength) was used
to irradiate each sample. Peak lists were generated using OMNIC
software v7.2a.
(Comparative) Example 1
Solid Form Disclosed in U.S. Pat. No. 7,129,232
[0077] A solution of
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox-
yimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazol-
io}methyl-3-cephem-4-carboxylate (36 g) in water was purified by
preparative HPLC utilizing ODS column. The eluate containing a
desired product was concentrated to about 1.5 L in vacuo. The
concentrate was adjusted to about pH 1 with concentrated
hydrochloric acid and chromatographed on Diaion.RTM. HP-20 (6 L)
eluting with 20% aqueous 2-propanol. The eluate was concentrated to
about 800 ml in vacuo, and 2M sulfuric acid (17 ml) was added. The
resulting solution was lyophilized to give a sulfuric acid salt as
an amorphous powder (23.6 g).
[0078] The powder was dissolved in water (71 ml) and ethanol (57
ml). After addition of seed crystals (310 mg), which resulted in
the precipitation of white solid, the mixture was stirred for 1
hour. A mixture of ethanol (47 ml) and water (37 ml) was added over
30 minutes, and ethanol (33 ml) was added over 20 minutes. Then the
slurry was stirred for an additional 1.5 hour. The precipitate was
collected by filtration, washed with ethanol/water (60 m1/20 ml)
and ethanol (60 ml) and dried to give
713-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimi-
no)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}m-
ethyl-3-cephem-4-carboxylic acid hydrogen sulfate as crystals (17.3
g).
[0079] IR(KBr) 3353, 3183, 1778, 1652, 1558, 1403, 1321, 1143,
1118, 997, 619 cm.sup.-1
[0080] .sup.1H-NMR (D.sub.2O) .delta. 1.61 (6H, s), 3.10-3.55 (6H,
m), 3.71 (3H, s), 5.02 and 5.23 (2H, ABq, J=16.7 Hz), 5.25 (1H, d,
J=4.9 Hz), 5.87 (1H, d, J=4.9 Hz), 7.91 (1H, s)
[0081] ESI-MS: m/z=667 (M+H.sup.+)
TABLE-US-00003 TABLE 3 X-ray powder diffraction analysis (by Rigaku
X-ray Diffraction system MultiFlex) 2.theta. intensity 8.0 1286
12.7 586 13.8 423 16.1 618 18.9 520 20.4 748 21.5 667 22.4 1058
23.3 944 24.0 618 25.5 813 26.7 472 27.9 537 28.5 455 31.3 390
X-ray: Cu/40 kV/30 mA
Example 2a
Novel Solid Form of Ceftolozane Sulfate
[0082] To obtain ceftolozane sulfate in Form 1: ceftolozane (1
molar equivalent) was dissolved in water to afford a solution at a
concentration of 80 g/L. An aqueous solution of sulfuric acid
(20-98%, 2.5 molar equivalents) was added at 0-20.degree. C. The
resulting solution was seeded with ceftolozane sulfate (0.01 to
0.05% by weight relative to active ceftolozane) and allowed to stir
for 1-3 hours at 0-20.degree. C. A precipitation was observed.
Isopropanol (20-40 volumes relative to active ceftolozane) was
added to result in a slurry at 0-20.degree. C. After filtration,
crystalline ceftolozane sulfate was obtained. The X-ray powder
diffraction pattern of the crystalline ceftolozane sulfate Form 1
is depicted in FIG. 1 (upper diffraction pattern), and the
corresponding data is summarized in Table 4. The Raman spectrum of
the crystalline ceftolozane sulfate Form 1 is depicted in FIG. 2
(upper spectrum), and the corresponding data is summarized in Table
5.
TABLE-US-00004 TABLE 4 X-ray Powder Diffraction Patterns for
Ceftolozane Sulfate Form 1 (Example 2a) Ceftolozane Sulfate Form 1
Angle [.degree.2.theta.] Intensity [cts] 4.061 629 8.126 3275 9.748
511 10.865 521 12.435 399 12.954 1225 14.016 867 14.284 613 16.177
937 16.413 1048 18.796 847 19.094 1024 20.200 484 20.596 1393
21.732 1260 22.278 1098 22.603 1816 23.490 1554 23.777 720 24.268
913 25.059 590 25.678 1261 25.929 1107 26.746 701 27.102 619 28.017
854 28.668 792 29.265 390 29.972 428 31.513 612 32.917 423 33.526
512 34.773 431 35.191 408 36.111 361 37.504 366 37.723 373 38.778
312 40.860 299 41.631 350 44.084 281 45.997 235
TABLE-US-00005 TABLE 5 Raman peak list for ceftolozane sulfate Form
1 (Example 2a) Ceftolozane Sulfate Form 1 Position (cm.sup.-1)
Intensity (Counts) 170.5 5.402 276.5 3.852 336.1 2.78 381.2 3.172
424 3.787 530.9 2.974 596.7 2.607 680.9 3.385 716.2 3.408 742.8
2.64 798.8 4.282 818.7 12.666 951.9 3.307 980.9 5.46 1055.3 1.794
1135.1 3.121 1242 2.471 1285 2.835 1328.5 3.402 1418.7 7.494 1464.1
15.996 1607.7 10.642 1642.3 8.252 1786 3.322 2893.8 5.886 2940.8
7.789 2976.1 8.658 3265.8 1.5
Example 2b
Novel Solid Form of Ceftolozane Sulfate
[0083] To obtain ceftolozane sulfate in Form 2: The ceftolozane
sulfate obtained as Form 1 in Example 2a was dried under vacuum and
nitrogen bleed at 20-25.degree. C. for 24-48 hours to afford
crystalline ceftolozane sulfate (vacuum-dried). The X-ray powder
diffraction pattern of the crystalline ceftolozane sulfate Form 2
is depicted in FIG. 1 (lower diffraction pattern), and the
corresponding data is summarized in the Table 6.
TABLE-US-00006 TABLE 6 X-Ray Powder Diffraction Pattern of
Ceftolozane Sulfate Form 2 (Example 2b) Ceftolozane Sulfate Form 2
Angle [.degree.2.theta.] Intensity [cts] 4.400 348 7.900 950 8.827
700 9.381 466 11.000 536 12.861 981 13.980 534 14.913 479 15.753
610 17.673 711 18.749 923 20.488 858 21.692 924 22.178 1020 24.235
1000 25.678 842 27.180 708 28.593 587 31.482 546 33.277 508 34.397
438 35.789 428 37.767 403
[0084] The Raman spectrum of the crystalline ceftolozane sulfate
Form 2 is depicted in FIG. 2 (lower spectrum), and the
corresponding data is summarized in Table 7. Table 7 lists the
Raman shift peaks for ceftolozane sulfate in solid Form 2.
TABLE-US-00007 TABLE 7 Raman peak list for ceftolozane sulfate form
2 (Example 2b) Ceftolozane Sulfate Form 2 Position (cm.sup.-1)
Intensity (Counts) 151 11.618 282 6.341 418.1 6.139 530.2 4.005
596.8 5.656 683.7 7.226 716.2 6.968 802.3 7.45 976.9 7.505 1174.2
3.974 1237 4.582 1282.1 6.944 1328.1 6.577 1414.3 12.424 1458.5
25.508 1602.2 20.204 1637.5 15.561 1782 5.388 2952.8 7.588
[0085] The moisture sorption/desorption property of crystalline
cefolozane sulfate form 2 is depicted in FIG. 5. A reversible
hysteresis associated with around 23% w/w water between 0% and 90%
relative humidity (RH) was observed. The DVS isotherm in FIG. 5 is
consistent with the presence of two crystalline forms that can be
interconverted as function of relative humidity. The presence of
ceftolozane sulfate solid Form 1 and ceftolozane sulfate solid Form
2 in the sample tested to obtain the DVS isotherm in FIG. 5 was
confirmed by a variable humidity XRPD (VH-XRPD) measurement, based
on the XRPD diffraction angles disclosed for Form 1 and Form 2 of
ceftolozane sulfate (as disclosed herein). Referring to DVS the
isotherm plot in FIG. 5, the lower curve corresponds to ceftolozane
sulfate in solid Form 2, and the upper curve is corresponds to
ceftolozane sulfate in solid Form 1. The Y-axis of the DVS plot is
change in mass. The X-axis of DVS plot refers to the percent
relative humidity (RH) of the sample. Reference point 10 in FIG. 5
is the starting point of Form 2 in DVS experiment. The lower
portion of the curve in FIG. 5 was obtained by measuring the change
in mass of a ceftolozane sulfate sample in solid Form 2 while
increasing relative humidity (RH) in the sample, starting at
reference point 10 of the lower curve from reference point 10 (Form
2) and moving toward reference point 20 (Form 1). Based on the data
collected, the ceftolozane sulfate in the sample converted from
Form 2 to Form 1 when the sample was exposed to conditions between
50% RH (reference point 12) and 70% RH (reference point 15).
Referring again to the lower curve in FIG. 5, ceftolozane sulfate
in Form 1 is present in the sample from 70% RH to reference point
20, where the sample is ceftolozane sulfate is in crystalline Form
1. Referring to the upper curve in FIG. 5, from reference point 20
to reference point 30, the ceftolozane sulfate in the sample
material remains as solid Form 1. From reference point 30 to around
20% RH (reference point 35 on the upper curve), the crystalline
form of ceftolozane sulfate in the material transforms from Form 1
to Form 2. As the relative humidity of the sample was dropped below
about 20% on the upper curve between reference point 30 and
reference point 40 (0% RH), the ceftolozane sulfate became more
amorphous, with some residual Form 2 remaining at reference point
40. In summary, the ceftolozane sulfate in the sample was present
as Form 2 at reference point 10 (40% RH), converted from Form 2 to
Form 1 between reference point 12 and reference point 15 on the
lower curve, remained as solid Form 1 between reference point 20
and reference point 30 on the upper curve, converted from Form 1 to
Form 2 between reference point 30 and reference point 35 on the
upper curve, and remained as solid Form 2 from reference point 35
to reference point 40 (with formation of amorphous solid form in
the sample). From reference point 40 to reference point 10 (lower
curve), increasing the relative humidity of the partially
crystalline Form 2 material resulted in material retaining some
ceftolozane sulfate in Form 2 (partially crystalline).
Example 2d
Representative Example of Process to Manufacture Novel Solid Forms
of Ceftolozane Sulfate
[0086] Using the process of steps 1-9 (below), active ceftolozane
sulfate Form 2 was obtained as a white solid, with a weight assay
of 76.2% (determined using HPLC method described with respect to
parameters in Table 9 herein) and purity of 98.7% AUC using HPLC
(determined using HPLC method discussed with respect to Table 10
herein). The ceftolozane sulfate solid Form 1 was produced by steps
1-8 in the procedure below, and further dried (step 9) to obtain
ceftolozane sulfate Form 2. The materials used in the process below
are summarized in Table 8a.
TABLE-US-00008 TABLE 8a MW Active Amount Volume Molar Step Material
(g/mol) (kg) (L) (L/kg) equiv. 1 Ceftolozane 666.7 55 650 N/A 1
solution 2 50% (w/w) 98.1 41 29 N/A 2.5 sulfuric acid 3 Ceftolozane
666.7 0.20 N/A N/A N/A sulfate seed 5 Isopropyl 60.1 N/A 1653 30
N/A alcohol (IPA) 8 IPA/Water (4:1) N/A N/A 221 4 N/A
[0087] 1. Polish filter (1 micrometer) the ceftolozane solution (85
g/L, 650 L) into a glass lined reactor and adjust the temperature
to 8-12 degrees C., with a target temperature of about 10 degrees
C. This temperature is maintained through step 6. [0088] 2. Charge
50% (w/w) sulfuric acid (41 kg, 29 L, 2.5 equiv) to the solution in
the reactor of step 1 over 10-30 minutes. [0089] 3. (optional, but
preferred step) Charge ceftolozane sulfate seed (200 g, 0.3% by
weight) to the reactor and stir the solution. (Note: nucleation was
observed upon seeding) [0090] 4. Age the batch in the reactor for 3
hours. [0091] 5. Charge isopropanol (IPA) (1650 L, 30 volumes) to
the reactor at a uniform rate of 4-5 vol/hr. (6-7 hours addition
time, target of 6.5 hours) (Note: if the rate of IPA addition is
not uniform, the purity levels of the product may be adversely
affected) [0092] 6. Stir the batch in the reactor for 1-6 hours,
target of 2 hours. [0093] 7. Filter the resulting ceftolozane
sulfate slurry from the reactor. [0094] 8. Wash the ceftolozane
slurry cake from step 7 with a solution of 4:1 IPA/water. (221 L, 4
volumes) [0095] 9. Dry the solid from step 8 under vacuum using a
dry nitrogen purge, with a nitrogen temperature of 15-35 degrees
C., target temperature of about 25 degrees C. The drying process
should be monitored by measuring for residual water and IPA levels
in the cake. The drying process can be completed when the residual
water content is less than about 8.5% and IPA levels are less than
about 5000 ppm. Typically, drying is complete within 48 hours.
Example 3
Comparative Ceftolozane Solvent Stability Test
[0096] This stability study was to evaluate stability and purity of
ceftolozane sulfate in different solvent systems.
[0097] Sample 1 was a solvent system used to prepare crystalline
ceftolozane sulfate from a mixture of isopropanol and water, as
described in Example 2b (in the absence of ethanol). Sample 2 was
solvent system used to obtain crystalline ceftolozane sulfate
prepared according to the procedure of U.S. Pat. No. 7,129,232,
wherein the crystals were precipitated from a mixture of ethanol
and water.
[0098] Sample 1 and sample 2 were maintained for 6 days (as
described in Example 2a, with continuous stirring). The purity of
ceftolozane in the samples in each solvent system was measured by
HPLC at day 0, day 3, and day 6.
[0099] Surprisingly, the purity of ceftolozane sulfate in sample 1
was significantly higher than the purity of ceftolozane sulfate in
sample 2 (see Table 8b).
TABLE-US-00009 TABLE 8b The purity of ceftolozane in ceftolozane
sulfate in different solvent systems used to obtain different solid
forms Sample 0 3 days 6 days 1 96.74% 87.39% 81.94% 2 96.84% 87.97%
67.74%
Example 4
Determination of Water Content for Crystalline Ceftolozane
[0100] Water content of crystalline ceftolozane sulfate (prepared
according to Example 2a as Form 1) was determined using a Mettler
Toledo Karl Fischer volumetric titrator V30 that was connected to a
Mettler Toledo Stromboli oven sample changer. AquaStar CombiTitrant
5 (EMD; Cat. No. 1.88005.1045; Lot No. 51096) was used as the
titrant and the AquaStar Combi-Methanol (EMD; Cat. No 1.88009.1045;
Lot No 53046) was used as the solvent. For data processing, the
LabX software version 3.1.1.0 was employed.
[0101] The Hydranal Water Standard for KF-Oven (Fluka; Cat. No.
34693; Lot No. SZBB010AV) that is expected to contain 5% water was
weighed accurately in duplicate at or very close to 200 mg. The
crystalline ceftolozane sulfate (15-18 mg) was weighed accurately
in triplicate in separate 20 mL Stromboli sample vials. The vials
were sealed with aluminum seals and rubber caps. A blank vial was
prepared by sealing an empty 20-mL Stromboli vial with the aluminum
seal and the rubber cap. The blank vial was used to determine the
background moisture in air inside the vial. All the vials were
loaded onto the Stromboli oven sample changer. Weights of the water
standard and the ceftolozane sulfate wet cake samples were entered
in grams into the titrator program sequence. The water standard and
the blank vial were equilibrated at 150.degree. C. The crystalline
ceftolozane sulfate samples were equilibrated at 130.degree. C.
Nitrogen flow at 40-50 mL/min was used to transport the moisture
through the transfer tube into the titator vessel. Mixing time of
180 s was used and the data acquisition was programmed with a
maximum start drift of 15 .mu.g/min. At the end of the runs, the
titrator software provided the water content in percent by weight.
The KF titrator passed the accuracy test as the mean of the
duplicate readings for the water standard was between the
acceptance range of 4.80-5.20%. Water content results for
crystalline ceftolozane sulfate derived from the triplicate
weighings were recorded and the mean was reported. The water
content determination follows the equation as described below. The
software described above provided the result directly after
factoring in the background moisture content without any need for
manual computation.
[0102] A sample of crystalline ceftolozane sulfate prepared
according to Example 1 was found to contain about 26.3% by weight
of water.
Example 5
Determining Concentration of Ceftolozane
[0103] Standards and samples are prepared in 50 mM sodium
perchlorate monohydrate, pH 4.00. A quantitation standard (Standard
Solution 1) and check standard (Standard Solution 2) are both
prepared at the target working concentration of 0.3 mg/mL taking
into consideration the potency, as-is of the standard. The samples
are prepared at the target active concentration of 0.3 mg/mL by
preparing a sample at 0.04% (w/v).
TABLE-US-00010 TABLE 9 HPLC Conditions for Concentration
Determination Column Develosil ODS-UG-5, 5 .mu.m, 250 mm .times.
4.6 mm, or Guard columns Develosil ODS-UG-5, 5 .mu.m, 10 mm .times.
4.0 mm, or Column 40.degree. C. .+-. 2.degree. C. temperature Mode
Gradient Mobile phase A 50 mM Sodium perchlorate monohydrate, pH
2.50 Mobile phase B 90% Acetonitrile in water Time (min) % A % B
Pump conditions 0.0 89.5.sup.a 10.5.sup.a 10.0 89.5.sup.a
10.5.sup.a 15.0 20 80 20.0 20 80 20.1 89.5.sup.a 10.5.sup.a 25.0
89.5.sup.a 10.5.sup.a Flow rate 1.0 mL/minute Detection UV at 254
nm Auto-sampler 4.degree. C. .+-. 2.degree. C. temperature
Injection volume 10 .mu.L Run time 25 minutes .sup.aThe ratio of
Mobile phase A to Mobile phase B may be adjusted to achieve the
desired retention time, however the isocratic ratio of % A to % B
must be identical for both isocratic intervals.
[0104] Standard Solution 1 is injected 6 times at the beginning of
the analysis to establish system suitability and precision.
[0105] System suitability is determined using the first injection
of Standard Solution 1. The tailing factor for the ceftolozane peak
be 0.8 to 1.5 and the retention time for the ceftolozane peak
should be 10.0 minutes.+-.1.5 minutes. The binary pump setting at
isocratic portions of the run (0.0 to 10.0 minutes and 20.1 to 25.0
minutes) may be adjusted to achieve the ceftolozane peak retention
time.
[0106] Additional suitability of the run is determined by: [0107] %
RSD of 6 Standard Solutionl injections must be less than 1.0% The
Standard Solution 2 recovery must be 100.0.+-.1.0%. [0108] The
retention time of Standard Solution 2 must be .+-.5% of the RT of
the first injection of Standard solution 1. [0109] The tailing
factor of ceftolozane in Standard Solution 2 must be 0.8 to
1.5.
[0110] Each sample is prepared in duplicate and injected in
singlet. The ratio of the response factor for the two preparations
must be within 100.0.+-.1.0%.
[0111] The mean ceftolozane potency, as is, is reported in .mu.g/mg
and calculated using the following equations:
Potency , as - is ( .mu. g / mg ) = Ac .times. Cstd .times. 1000
.times. Vc Astd .times. Wc , ##EQU00001##
[0112] where:
[0113] Ac=Ceftolozane peak area in sample chromatogram;
[0114] Cstd=Ceftolozane Standard 1 concentration, mg/mL;
[0115] Astd=Average peak area in 6 injection of standard 1;
[0116] Wc=Sample weight, mg;
[0117] Vc=Sample volume, mL;
[0118] 1000=Conversion from mg to .mu.g; and
Mean Potency , as - is ( .mu. g / mg ) = ( Preparation 1 +
Preparation 2 ) 2 . ##EQU00002##
[0119] The mean ceftolozane assay, anhydrous and sulfuric acid
free, is reported in % and calculated using the following
equation:
Mean Assay(%)=Potency.times.101(100-Water Content-Sulfuric
Acid);
[0120] where:
[0121] Potency=Mean Potency, as-is, .mu.g/mg;
[0122] Water Content=Mean water content, %; and
[0123] Sulfuric Acid=Mean sulfuric acid content, %.
Example 6
Determining Water Content of Ceftolozane
[0124] Testing for water content is performed using a Stromboli
oven and volumetric titrator in triplicate using separate weighing
of 180 mg of ceftolozane sulfate. The test sample is extracted at
130.degree. C., moisture is transferred to the titration vessel and
titrated to the potentiometric end point. The percent moisture is
calculated based on the weight of the sample, and the average of
the three values is reported.
Example 7
Determination of the Purity of Ceftolozane Sulfate
[0125] Ceftolozane sulfate samples are prepared at a concentration
of 1 mg/mL in diluent (50 mM sodium perchlorate monohydrate, pH
4.00). The system suitability standard (SST) is prepared at a
concentration of 1 mg/mL of ceftolozane sulfate containing
specified impurities in diluent (50 mM sodium perchlorate
monohydrate, pH 4.00). Ceftolozane samples and SST are stored in a
refrigerated autosampler tray at 4.+-.2.degree. C. and the samples
are only stable for 5 hours at this condition. The HPLC conditions
are listed in Table 10.
TABLE-US-00011 TABLE 10 HPLC Conditions for HPLC-RT, Related
Substances, and Purity Method Column Develosil ODS-UG-5, 5 .mu.m,
250 mm .times. 4.6 mm, or equivalent Guard column Develosil
ODS-UG-5, 5 .mu.m, 10 mm .times. 4.0 mm, or equivalent Column
45.degree. C. .+-. 2.degree. C. temperature Mode Gradient Mobile
phase A 50 mM Sodium perchlorate monohydrate, pH 2.50 Mobile phase
B 63 mM Sodium perchlorate monohydrate, pH 2.50:ACN 80:20 Time
(min) % A % B Pump conditions 0.0 97.5 2.5 3.0 73.0.sup.a
27.0.sup.a 33.0 68.0.sup.a 32.0.sup.a 63.0 0.0 100 88.0 0.0 100
88.1 97.5 2.5 105.0 97.5 2.5 Flow rate 1.0 mL/minute Detection UV
at 254 nm Auto-sampler 4.degree. C. .+-. 2.degree. C. temperature
Injection volume 10 .mu.L Run time 105 minutes .sup.aThe ratio of
mobile phase A to mobile phase B from 3 to 33 minutes may be
adjusted to achieve the desired retention times.
[0126] At the beginning of each run, the diluent blank and SST are
each injected in singlet. The system suitability is determined
using the SST. The tailing factor for the ceftolozane peak should
be between 0.8 and 1.5, and the retention time for the ceftolozane
peak should be 24.0 minutes.+-.1.0 minutes. The binary pump setting
between 3.0 and 33.0 minutes may be adjusted to achieve the
ceftolozane peak retention time.
[0127] Each sample is prepared in singlet and injected twice. Only
impurities >LOD (0.008% Area) are integrated. The peak area
percentage for each impurity >LOD is taken directly from the
chromatogram. The mean % area of each peak is calculated and the
absolute difference of any peak in the two replicates cannot be
>0.030%. The purity and related substances are determined based
on relative area % of each peak with respect to the total peak area
of the sample. The total impurities are the sum of the individual
impurities >LOD. The calculations are as follows:
% Impurity ( % Area ) = Area impuity Area Total .times. 100 % ,
##EQU00003##
[0128] where:
[0129] Area.sub.Impurity=Area of the Individual Impurity Peak;
and
[0130] Area.sub.Total=Total Area of all peaks >LOD including
Ceftolozane.
Purity ( % Area ) = Area Ceftolozane Area Total .times. 100 % ;
##EQU00004##
[0131] where:
[0132] Area.sub.Ceftolozane=Area of the Ceftolozane Peak; and
[0133] Area.sub.Total=Total Area of all peaks >LOD including
Ceftolozane.
Total Impurities(% Area)=100-Purity(% Area).
[0134] Individual specified impurities equal to or above the limit
of quantitation (LOQ) (0.027% Area) are reported. Individual
unspecified impurities equal to or above 0.03% are also
reported.
Example 8
Lyophilization of Ceftolozane Solid Forms
[0135] Sterile ceftolozane compositions suitable for combination
with tazobactam to form a pharmaceutical composition are prepared
as a lyophilized powder from the ceftolozane sulfate comprising
solid Form 2 by compounding the drug substance with excipients into
an aqueous solution, aseptically filtering the solution,
lyophilizing the solution, then grinding, sieving and packaging the
sterile lyophilized powder. The physical stability of the bulk
solution at varying concentrations was examined and concentrations
up to 150 mg ceftolozane free base/g solution were found suitable.
All the registration batches were prepared using 150 mg/g
ceftolozane concentration in the compounding solution and this
concentration is proposed for commercial manufacturing. The
resulting ceftolozane composition solubility was assessed in a
concentration range proposed for manufacturing, in the presence of
excipients intended for use in the ceftolozane formulation for use
in the pharmaceutical composition. For each sample, the ratio of
active to inactive ingredients was conserved. Samples were adjusted
to pH 6.9, held at 2 to 8.degree. C., and visually assessed for any
precipitation. The results are reported in Table 11.
TABLE-US-00012 TABLE 11 Ceftolozane Precipitation Time as Function
of Solution Concentration, 2 to 8.degree. C. Ceftolozane Sulfate
Ceftolozane Free Base Concentration, mg/g Concentration, mg/g Time
to Precipitate 200 174 2 hours 189 165 <18 hours 178 156 >24
hours.sup.i) 172 150 >48 hours 149 130 >24 hours.sup.a
.sup.i)Last observation was made at 24 hour; no sign of
precipitation was noticed
[0136] Based on these observations, ceftolozane bulk solution with
up to 150 mg ceftolozane free base/g solution can be held at 2 to
8.degree. C. for up to 48 hours without affecting its solubility.
The suitability of compounding to 150 mg ceftolozane free base/g
solution at 10.+-.2.5.degree. C. was confirmed during the
manufacturing of batches on the laboratory, pilot and engineering
scale. Refer to Table 12 for solution stability data. The purity
data in Table 12 was generated using a modified version of the HPLC
method that is described in Table 10. As part of the modification,
the initial mobile phase composition comprised 75% mobile phase A
and 25% mobile phase B. This composition was ramped to 70% mobile
phase A and 30% mobile phase B in 30 minutes followed by a ramp to
100% mobile phase B over another 30 minutes. The 100% mobile phase
B was then held constant for 25 minutes, after which the mobile
phase composition was reverted back in 0.1 minutes to initial
conditions of 75% mobile phase A and 25% mobile phase B. Column
equilibration was performed at the initial mobile phase composition
for up to 110 minutes, thereby giving a total HPLC run time of 110
minutes. The limit of quantification determined for the method with
the conditions described above was 0.015% and therefore all
individual specified impurities equal to or above 0.015% were
reported.
[0137] A compounding temperature of 10.+-.2.5.degree. C. was
targeted to maintain ceftolozane purity. To confirm the compounding
solution stability, a study was conducted in which ceftolozane was
prepared according to the proposed commercial process and held at
10.+-.2.5.degree. C. for up to 2 days. The solution was sampled and
tested for ceftolozane potency and purity/impurities. The results
are provided in Table 12. The data indicated ceftolozane impurity
profile was essentially unchanged from initial and none of the
individual related substances increases more than 0.10%. Therefore,
a 24 hour maximum hold time is proposed for the commercial
process.
TABLE-US-00013 TABLE 12 Effect of Hold Time on Purity/Impurity
Profile of Ceftolozane Bulk Solution Time from Compounding t.sub.0
4 h 18 h 24 h Day 2 Total Purity, % 98.7 98.8 98.6 98.6 98.7 Total
Impurities, % 1.3 1.2 1.4 1.4 1.3
[0138] The ceftolozane bulk solution is rendered aseptic via
sterilizing filtration. For routine commercial manufacturing, the
compounded solution will be first filtered through a bioburden
reduction filter, 0.45 .mu.m, then sterile filtered through two
0.22 .mu.m filters in sequence and the filter integrity of the 0.22
.mu.m filters will be assessed during manufacturing.
[0139] Through a series of studies on both the pilot and commercial
scale lyophilization equipment, the lyophilization process was
developed and shown to be suitable: across a range of solution
concentrations, at a variety of lyophilizer tray fill depths,
following an array of lyophilization cycle parameters, in a number
of lyophilizers, of both laboratory and commercial scale, and in
two different commercial lyophilization suites.
[0140] In particular, six different lyophilizers (one pilot
lyophilizer and five commercial lyophilizers from two separate
commercial suites) have been used to make acceptable ceftolozane
material using concentrations as high as 150 mg ceftolozane free
base/g solution, fill depths from 1 to 3 cm, and different cycle
parameters, including primary and/or secondary drying temperatures
as high as 40.degree. C. Based on these studies, freezing the
product to at least -40 to -45.degree. C. was considered an
appropriate target. Primary drying temperatures are also typically
set based on the glass transition temperature of the frozen bulk
solution to minimize collapse. However, on occasion, the collapse
may be prevented by using primary drying temperatures that are
dictated by the full melt temperature, vs. the glass transition
temperature. Therefore, studies were performed to examine these two
temperatures more closely, to determine which would be controlling
to prevent collapse. A variety of lyophilization conditions and
instrumentation have been shown to be robust across a range of
lyophilization conditions. Therefore, the preferred lyophilization
cycles for producing lyophilized ceftolozane compositions from a
solution comprising ceftolozane sulfate solid Form 2 have one or
more of the following characteristics: (1) not more than 150 mg
ceftolozane free base/g bulk solution concentration, (2) no more
than 3 cm fill depth, (3) cycle parameters including: freezing to
at least -40 to -45.degree. C., (4) drying to no more than
40.degree. C., (4) single- or multi-step drying and setting chamber
pressure during the start of primary drying at not more than 400
.mu.bar.
Example 9
Preferred Pharmaceutical Composition Comprising Ceftolozane and
Tazobactam ("Representative Ceftolozane/Tazobactam Product")
[0141] Pharmaceutical compositions comprising ceftolozane and
tazobactam can be obtained as described herein. A Representative
Ceftolozane/Tazobactam Product is described in Table 14 below
(ceftolozane and tazobactam for injection) as an injectable
antibacterial combination product consisting of the cephalosporin
antibacterial ceftolozane sulfate and the beta-lactamase inhibitor
tazobactam sodium for intravenous administration.
TABLE-US-00014 TABLE 13 Excipients Used in Ceftolozane composition
Inactive Concentration Ingredients Amount, in Infusion Rationale
for Database Component Function mg/Vial Solution, % Inclusion (IID)
Range Citric acid Chelating 21 0.02 Used to prevent 0.0025 to 50%
agent discoloration and degradation Sodium Stabilizing 487 0.49
Used as a 0.187 to 45% Chloride agent stabilizing agent for
ceftolozane sulfate L-arginine Alkalizing 600.sup.i) 0.60 Used to
adjust 0.29 to 88% agent Q.S. for ceftolozane pH solution pH
adjustment .sup.i)L-arginine is added as needed to achieve pH 6.5
.+-. 0.5; 600 mg per vial is considered a representative total
amount.
TABLE-US-00015 TABLE 14 Unit Compositions of Ceftolozane/
Tazobactam for Injection, 1000 mg/500 mg Nominal Composition
Component Function mg per Vial Ceftolozane Ceftolozane Active 1147
composition.sup.1) Sulfate (Solid Form 2) Citric Acid, Chelating
Agent 21 Anhydrous Sodium Stabilizing Agent 487 Chloride L-Arginine
Alkalizing Agent 600.sup.2) Q.S. for pH adjustment Tazobactam
Sodium.sup.3) Active 537 Nitrogen Processing Aid.sup.ii) Q.S. Total
Weight 2792 .sup.1)Actual amount of ceftolozane composition will
vary based on the measured potency. Ceftolozane sulfate, 1147 mg,
corresponds to 1000 mg ceftolozane free base. .sup.2)L-arginine is
added as needed to achieve pH 6.5 .+-. 0.5; 600 mg per vial is
considered a representative total amount. .sup.3)Actual weight of
tazobactam sodium will vary based on the measured potency.
Tazobactam sodium 537 mg, corresponds to 500 mg tazobactam free
acid 4) Nitrogen blanket is applied after powders are dispensed to
the vial and prior to insertion of stopper.
[0142] A first aqueous solution comprising ceftolozane sulfate Form
2 and the ingredients in the ceftolozane composition in Table 13 is
lyophilized in the absence of tazobactam to provide the lyophilized
ceftolozane composition. The first aqueous solution comprises
ceftolozane sulfate and the specific excipients in the preferred
compositions, in an amount per unit dosage form provided by the
quantities and functions as provided in Table 14. All excipients
are compendial and typical for sterile pharmaceutical dosage forms,
requiring no additional treatment prior to use in the formulation.
The excipients are used in levels within the range established in
other FDA approved products as described in the Inactive
Ingredients Database (IID). A second solution comprising tazobactam
acid and sodium bicarbonate is lyophilized in the absence of
ceftolozane to obtain the Tazobactam Sodium Composition in Table
14. Subsequently, the lyophilized Tazobactam Sodium Composition is
dry blended with the lyophilized Ceftolozane composition comprising
tazobactam sodium and ceftolozane sulfate in a weight ratio
providing 500 mg of tazobactam acid equivalent per 1,000 mg of
ceftolozane active equivalent.
Example 10
Reconstitution of Ceftolozane/Tazobactam Preparation Prior To
Administration to a Subject
[0143] The ceftolozane/tazobactam composition of Example 9 was
reconstituted prior to intravenous (IV) administration. In
accordance with one embodiment of the method of treatment,
immediately prior to injection into a patient, a single vial,
containing 1500 mg ceftolozane and tazobactam, was reconstituted
with 20 mL 0.9% NaCl (normal saline) and diluted into a 80 mL bag
of sterile water for injection for a total volume of 100 mL.
[0144] The ceftolozane and tazobactam composition was reconstituted
in accordance with the procedure as follows:
[0145] Obtain 1 vial of ceftolozane/tazobactam unit dosage form,
1500 mg/vial. Record the site and subject number and time and date
of preparation in the spaces provided on the vial label.
Ceftolozane/tazobactam of Example 9 does not contain a
bacteriostatic preservative. Aseptic technique must be followed in
preparing the infusion solution.
[0146] Aseptically reconstitute a lyophilized vial of
ceftolozane/tazobactam unit dosage form, 1500 mg with 10 ml water
for injection or 0.9% Sodium Chloride for injection, USP (normal
saline) and gently shake to dissolve. The final volume is
approximately 11.4 mL. The resultant concentration is approximately
132 mg/mL.
[0147] Using aseptic technique, withdraw the entire contents
(approximately 11.4 mL) of the reconstituted vial using a syringe
and add it to an infusion bag containing 100 mL of 0.9% Sodium
Chloride for Injection, USP (normal saline) or 5% Dextrose
Injection, USP. Ensure the entire volume of the reconstituted vial
is added to the infusion bag.
[0148] Gently swirl the contents of the IV bag to ensure complete
mixing and dissolution of the drug. The final volume of diluted
ceftolozane/tazobactam unit dosage form of Example 9 for infusion
will be .about.111 ml. The entire contents of the infusion bag of
ceftolozane/tazobactam is administered to each subject. This means
that the infusion line is flushed with sterile saline to completely
administer the proper dose).
[0149] Inspect the infusion bag for excess air, visible
contamination and leaks. The diluted solution should be clear.
[0150] Upon constitution with sterile water for injection or 0.9%
sodium chloride (normal saline) injection, the
ceftolozane/tazobactam solution in the vial may be held for 1-hour
prior to transfer and dilution in the infusion bag.
[0151] Following dilution of the solution with normal saline or 5%
dextrose, the ceftolozane/tazobactam solution obtained from the
ceftolozane/tazobactam composition of Example 9 is stable for 24
hours when stored at room temperature or 10 days when stored under
refrigeration at 2 to 8.degree. C. (36 to 46.degree. F.).
Example 11
Melting Point of Ceftolozane Sulfate Form 2
[0152] Melting point experiment was performed for ceftolozane
sulfate form 2 using the SRS Optimelt melting point apparatus.
SRS-certified vanillin and phenacetin were used to verify the
system performance. The temperature scan from 100.degree. C. to
400.degree. C. was performed for ceftolozane sulfate. The material
decomposed prior to melting. The decomposition, as indicated by the
distinct change in color, appeared to commence at about 170.degree.
C.
Example 12
TGA and DSC of Ceftolozane Sulfate Form 2
[0153] Thermogravimetric analysis (TGA) and differential scanning
calorimetry (DSC) thermograms are shown in FIG. 3 and FIG. 4,
respectively. An initial weight loss of 6.8% observed in the TGA
thermogram from initial temperature to 181.degree. C. is consistent
with the content of water and residual isopropanol present in
ceftolozane sulfate, lot 440637 0004 2. Analysis of the thermogram
beyond 181.degree. C. indicated that ceftolozane sulfate likely
undergoes degradation beyond this temperature. The DSC thermogram
exhibited a broad endotherm with the minima at about 105.49.degree.
C. The subsequent exotherm in the thermogram is indicative of
decompostion that is consistent with the observation in the melting
point experiment.
Example 13
Hygroscopicity of Ceftolozane Sulfate Form 2
[0154] Hygroscopicity of ceftolozane sulfate, Form 2 was assessed
using the SMS DVS Intrinsic moisture sorption analyzer equipped
with a calibrated Rotronic probe. The temperature was maintained at
25.degree. C. and the material was exposed to relative humidity
from 0 to 90%. Ceftolozane sulfate showed continuous adsorption of
water through the cycle with total uptake of 23% at 90% relative
humidity indicating that ceftolozane sulfate is hygroscopic.
* * * * *