SOLID FORMS OF CEFTOLOZANE
Novel solid forms of ceftolozane are described, as well as methods for the preparation and use of these solid forms.
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 −1 ) at about 171 cm −1 , 743 cm −1 , 819 cm −1 , 1055 cm −1 , 2894 cm −1 and 2976 cm −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 −1 ) at about 597 cm −1 , 716 cm −1 and 1329 cm −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 −1 ) at about 171 cm −1 , 743 cm −1 , 819 cm −1 , 1055 cm −1 , 2894 cm −1 and 2976 cm −1 .
6 . The solid form of ceftolozane sulfate of claim 3 that produces additional Raman shift peaks (±5 cm −1 ) at about 171 cm −1 , 743 cm −1 , 819 cm −1 , 1055 cm −1 , 2894 cm −1 and 2976 cm −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° C. during the lyophilization cycle,
d. drying to no more than 40° C., and
e. single- or multi-step drying and setting chamber pressure during the start of primary drying at not more than 400 μbar.
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 −1 ) at about 597 cm −1 , 716 cm −1 and 1329 cm −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 −1 ) at about 597 cm −1 , 716 cm −1 and 1329 cm −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.