Solid forms of ceftaroline and methods of preparation

Abstract

The present invention relates to a novel solid form of Ceflupozon sulfate (DMAc solvate of Ceflupozon sulfate (Form 3)), compositions comprising the DMAc solvate of Ceflupozon sulfate (Form 3), synthesis of Form 3 and improved crystallization processes using Form 3 to prepare Form 2 of Ceflupozon sulfate. The novel compositions also include Form 3 of Ceflupozon sulfate and / or other crystalline and amorphous solid forms of Ceflupozon.

Description

Background of the Invention

[0002] Cefoloza sulfate is an example of a pharmaceutically acceptable salt of cefoloza, a cephalosporin antibacterial agent, and has the chemical name (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-onthiol-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)-imino]acetyl [4.2.0]oct-2-en-2-carboxylate (5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureo]-2-methyl-1-pyrazoliumyl}methyl-3-cephalosporin-4-carboxylate. It is also known as CXA-101 or FR264205. The structure of cefoloza sulfate is shown below.

[0003]

[0004] Cefoloza and its synthesis method are described in U.S. Patent 7,129,232. A composition comprising cefoloza sulfate and tazobactam sodium (ZERBAXA®) is intended for intravenous administration or infusion to treat bacterial infections.

[0005] Current methods for manufacturing cefuroxime involve a three-step purification sequence consisting of column chromatography, nanofiltration, and crystallization to obtain the active pharmaceutical ingredient (API) cefuroxime, also known as cefuroxime form 2 (WO 2015 / 048217 and WO2016 / 109259). Although the column chromatography and nanofiltration steps yield cefuroxime form 2 with high purity, the entire process is time-consuming, has low volumetric efficiency, low yield, and requires specialized manufacturing equipment. Furthermore, this method is hampered by slow filtration rates, which significantly reduces its productivity.

[0006] There remains a need for simplified and improved manufacturing methods for cefoloza sulfate. As described herein, a new solid form (Form 3) of cefoloza sulfate provides the basis for a simplified purification method. This solid form, the DMAc solvate of cefoloza sulfate (referred to herein as "Form 3"), enables a crystallization-based purification method that replaces existing column chromatography and nanofiltration methods. The new method offers higher yields, significantly reduced solvent consumption, shorter cycle times, and utilizes standard manufacturing equipment, resulting in a more productive, environmentally friendly, and lightweight manufacturing process. Furthermore, the streamlined purification method reduces overall manufacturing time, ultimately saving costs and reducing energy consumption. Invention Overview

[0008] This invention relates to a novel solid form of cefoloza sulfate (a DMAc solvate of cefoloza sulfate (Form 3)), compositions comprising cefoloza sulfate DMAc solvate (Form 3), the synthesis of Form 3, and an improved crystallization method using Form 3 to prepare Form 2. The novel compositions also include cefoloza sulfate solid form 3 and / or other crystalline and amorphous solid forms of cefoloza.

[0009] The DMAc solvate of cefoloza sulfate, referred to as Form 3, can be present in a wet phase (referred to herein as "Form 3A"), a dry phase (referred to herein as "Form 3B"), or a mixture thereof. As used herein, the term "Form 3" refers to Form 3A, Form 3B, and / or a mixture thereof.

[0010] A novel solid form of cefuroxime (form 3A) of cefuroxime sulfate DMAc solvate can be identified by X-ray powder diffraction (XRPD) with one or more characteristic diffractions at angles (2θ ± 0.2) of 12.8, 17.5, 21.7, 24.0, and 24.6. Furthermore, solid form 3A of cefuroxime also exhibits additional diffraction at angles (2θ ± 0.2) of 9.4, 18.9, 24.0, 25.7, and 26.9.

[0011] The novel solid form of cefoloza sulfate DMAc solvate (form 3B) can be identified by X-ray powder diffraction (XRPD) with one or more characteristic diffractions at angles of 11.0, 21.0, 22.5 and 24.0 (2θ ± 0.2).

[0012] In a first embodiment of the invention, cefoloza sulfate DMAC solvate (form 3A) is obtained by a method comprising the following steps:

[0013] a) Combine cefoloza TFA, water, DMAc and the first cosolvent to form a slurry;

[0014] b) Filter the slurry to produce filtrate;

[0015] c) Combine the filtrate and sulfate source;

[0016] d) Add a second cosolvent and DMAc to solvate the seed to produce the product;

[0017] e) Filter the product to obtain wet solids of cefoloza sulfate DMAc solvate (form 3A).

[0018] In a further embodiment of the invention, cefoloza sulfate DMAC solvate (form 3B) is obtained by drying cefoloza sulfate DMAc solvate (form 3A) in step e) to produce a dry solid of cefoloza sulfate DMAc solvate (form 3B).

[0019] In a further embodiment, iodine and xanthate are added to the slurry of step a). In one embodiment, the xanthate is potassium isopropyl xanthate (PIX), sodium isopropyl xanthate (SIX), potassium ethyl xanthate, sodium ethyl xanthate, potassium tert-butyl xanthate, or sodium tert-butyl xanthate. In a further embodiment, the xanthate is potassium isopropyl xanthate (PIX).

[0020] In a second embodiment of the invention, the solid form of cefoloza sulfate (form 2) is obtained by a method comprising the following steps:

[0021] a) Combine cefoloza sulfate DMAc solvate (form 3), acetonitrile, and water to produce a solution;

[0022] b) Add sulfuric acid into the solution;

[0023] c) Filter the solution and add cefoloza sulfate seed crystals to produce a slurry;

[0024] d) Add the antisolvent to the slurry;

[0025] e) Add alkali to the slurry to adjust the pH;

[0026] f) The slurry is filtered and washed with a solvent mixture to produce wet crystals of cefoloza sulfate (Form 1);

[0027] g) Dry the wet crystals of cefuroxime sulfate to produce the solid form of cefuroxime sulfate (Form 2).

[0028] In this second embodiment, the wet solid of cefuroxime sulfate DMAc solvate, the dry solid of cefuroxime sulfate DMAc solvate, or a mixture thereof can be used in step a) above.

[0029] In a further embodiment, prior to drying in step g), the wet crystals of cefoloza sulfate (Form 1) are washed with acetone.

[0030] A third embodiment of the present invention is a method for preparing a wet solid (form 3A) of cefoloza sulfate DMAc solvate, comprising the following steps:

[0031] a) Combine cefoloza TFA, water, DMAc and the first cosolvent to form a slurry;

[0032] b) Filter the slurry to produce filtrate;

[0033] c) Combine the filtrate and sulfate source;

[0034] d) Add a second cosolvent and DMAc to solvate the seed to produce the product; and

[0035] e) Filter the product to obtain wet solids of cefoloza sulfate DMAc solvate (form 3A).

[0036] In a further embodiment, after filtration in step e), the wet solid of cefuroxime sulfate DMAc solvate (form 3A) is dried to produce a dry solid of cefuroxime sulfate DMAc solvate (form 3B).

[0037] In a further embodiment, after step a), iodine and xanthate are added to the slurry of step a). In one embodiment, the xanthate is potassium isopropyl xanthate (PIX), sodium isopropyl xanthate (SIX), potassium ethyl xanthate, sodium ethyl xanthate, potassium tert-butyl xanthate, or sodium tert-butyl xanthate. In a further embodiment, the xanthate is potassium isopropyl xanthate (PIX).

[0038] A fourth embodiment of the present invention is a method for preparing cefoloza sulfate in solid form (form 2), comprising the following steps:

[0039] a) Combine cefoloza sulfate DMAc solvate (form 3), acetonitrile, and water to produce a solution;

[0040] b) Add sulfuric acid into the solution;

[0041] c) Filter the solution and add cefoloza sulfate seed crystals to produce a slurry;

[0042] d) Add the antisolvent to the slurry;

[0043] e) Add alkali to the slurry to adjust the pH;

[0044] f) Filter the slurry and wash it with a solvent mixture to produce wet solids (Form 1);

[0045] g) Dry the wet crystals to produce cefoloza sulfate in solid form (Form 2).

[0046] These manufacturing methods can be used to produce antibiotic compositions containing cefoloza in solid form suitable for treating infections. In some embodiments, wet solid cefoloza sulfate (Form 3A), dry solid cefoloza sulfate (Form 3B), or mixtures thereof can be used. For example, a cefoloza-containing pharmaceutical composition for parenteral administration can be obtained from cefoloza sulfate (Form 2) using cefoloza DMAc solvates (Form 3A, Form 3B, or mixtures thereof) by a method comprising the following steps: (a) converting the cefoloza DMAc solvates (Form 3A, Form 3B, or mixtures thereof) to cefoloza sulfate (Form 2), (b) forming a cefoloza solution containing cefoloza sulfate (Form 2) in water, and (c) lyophilizing the cefoloza solution to obtain a lyophilized cefoloza sulfate composition. The lyophilized cefoloza sulfate composition can be combined with tazobactam (or a pharmaceutically acceptable salt thereof) to obtain a pharmaceutical composition suitable for intravenous administration after reconstitution. Brief description of the attached diagram

[0048] Figure 1 Thermogravimetric analysis (TGA) curves of the dry solid form of cefoloza sulfate DMAC solvate, referred to in this paper as form 3B, are depicted.

[0049] Figure 2 Differential scanning calorimetry (DSC) thermogram of the dry solid form of cefoloza sulfate DMAC solvate, referred to herein as form 3B.

[0050] Figure 3 This is an X-ray powder diffraction pattern of wet-phase cefoloza sulfate DMAC solvate (form 3A).

[0051] Figure 4 This is an X-ray powder diffraction pattern of dry-phase cefoloza sulfate DMAC solvate (form 3B).

[0052] Figure 5 Describe the filtration times of two different cefoloza sulfate forms 1 slurries prepared from acetonitrile / water or 2-propanol / water.

[0053] Figure 6A This is an example of a synthetic scheme demonstrating a known method for synthesizing cefoloza TFA.

[0054] Figure 6B This is a synthetic scheme for preparing the starting material (protected 5-amino-1-methylpyrazole) for cefoloza. Invention Details

[0056] This invention relates to a novel solid form (Form 3) of cefoloza sulfate DMAc solvate, a method for preparing such a form, and a method for manufacturing cefoloza sulfate Form 1 using Form 3, and then converting it to Form 2 (the cefoloza API used in ZERBAXA® (cefoza / tazobactam)). Unless otherwise stated, the novel solid form of this invention may be a crystalline form, an amorphous form, or a mixture thereof.

[0057] In a first embodiment of the invention, cefoloza sulfate DMAC solvate (form 3A) is obtained by a method comprising the following steps:

[0058] a) Combine cefoloza TFA, water, DMAc and the first cosolvent to form a slurry;

[0059] b) Filter the slurry to produce filtrate;

[0060] c) Combine the filtrate and sulfate source;

[0061] d) Add a second cosolvent and DMAc to solvate the seed to produce the product;

[0062] e) Filter the product to obtain wet solids of cefoloza sulfate DMAc solvate (form 3A).

[0063] In one embodiment, the first cosolvent and the second cosolvent are independently selected from ketones, C2-C5 alcohols, nitriles, amides, ethers, and other miscible solvents. In another embodiment, the first cosolvent and the second cosolvent are independently selected from acetonitrile, isopropanol, tert-amyl alcohol, 1-propanol, ethanol, tert-butanol, dioxane, THF, and other miscible solvents. In one embodiment, the first cosolvent and the second cosolvent are independently selected from acetonitrile, isopropanol, and tert-amyl alcohol. In another preferred embodiment, the first cosolvent and the second cosolvent are acetonitrile.

[0064] In another embodiment, the sulfate source is selected from sulfuric acid, ammonium bisulfate, ammonium sulfate, sodium bisulfate, potassium bisulfate, lithium bisulfate, magnesium bisulfate, tetrabutylammonium bisulfate, etc. In a further embodiment, the sulfate source is selected from ammonium bisulfate, ammonium sulfate, sodium bisulfate, potassium bisulfate, lithium bisulfate, and tetrabutylammonium bisulfate. In a further embodiment, the sulfate source is selected from ammonium bisulfate.

[0065] In a further embodiment, the cefoloza sulfate seed crystals are selected from form 3A, form 3B, or a mixture thereof.

[0066] In a further embodiment, iodine and xanthate are added to the slurry of step a). In one embodiment, the xanthate is potassium isopropyl xanthate (PIX), sodium isopropyl xanthate (SIX), potassium ethyl xanthate, sodium ethyl xanthate, potassium tert-butyl xanthate, or sodium tert-butyl xanthate. In a further embodiment, the xanthate is potassium isopropyl xanthate (PIX).

[0067] In some embodiments, cefoloza TFA is treated with xanthate and iodine to provide cefoloza DMAc sulfate solvate (form 3) with a palladium level of less than 1 ppm. Typically, cefoloza TFA contains about 100 ppm palladium. To consistently reduce the palladium level to a pharmaceutically acceptable level, cefoloza TFA is first dissolved in water or a water / organic mixture and then treated with about 0.1 to 10 mol% xanthate (e.g., PIX or SIX) and 0.1 to 5 mol% iodine to produce a slurry containing palladium solids. These palladium solids are filtered, and the resulting batch undergoes crystallization to obtain cefoloza DMAc sulfate solvate with a residual palladium of less than 1 ppm.

[0068] In a further embodiment of the invention, cefoloza sulfate DMAC solvate (form 3B) is obtained by drying cefoloza sulfate DMAc solvate (form 3A) in step e) to produce a dry solid of cefoloza sulfate DMAc solvate (form 3B).

[0069] In a second embodiment of the invention, the solid form of cefoloza sulfate (form 2) is obtained by a method comprising the following steps:

[0070] a) Combine cefoloza sulfate DMAc solvate (form 3), acetonitrile, and water to produce a solution;

[0071] b) Add sulfuric acid into the solution;

[0072] c) Filter the solution and add cefoloza sulfate seed crystals to produce a slurry;

[0073] d) Add the antisolvent to the slurry;

[0074] e) Add alkali to the slurry to adjust the pH;

[0075] f) The slurry is filtered and washed with a solvent mixture to produce wet crystals of cefoloza sulfate (Form 1);

[0076] g) Dry the wet crystals of cefuroxime sulfate to produce the solid form of cefuroxime sulfate (Form 2).

[0077] In this second embodiment, the wet solid of cefuroxime sulfate DMAc solvate, the dry solid of cefuroxime sulfate DMAc solvate, or a mixture thereof can be used in step a) above.

[0078] In a further embodiment, prior to drying in step g), the wet crystals of cefoloza sulfate (Form 1) are washed with acetone.

[0079] In a further embodiment, the cefoloza sulfate seed crystals are selected from form 1, form 2, or a mixture thereof.

[0080] In one embodiment, the antisolvent is selected from C1-C5 alcohols, nitriles, ethers, and other miscible solvents. In another embodiment, the antisolvent is selected from acetonitrile, isopropanol, tert-amyl alcohol, 1-propanol, ethanol, tert-butanol, dioxane, methyl tert-butyl ether (MTBE), THF, and other miscible solvents. In a further embodiment, the antisolvent is selected from acetonitrile.

[0081] In one embodiment, the base is an inorganic or organic base. In a further embodiment, the base is selected from amine bases. In a further embodiment, the base is triethylamine.

[0082] In one embodiment, the solvent mixture is a mixture of water and an antisolvent. In a further embodiment, the solvent mixture is a mixture of water and acetonitrile.

[0083] In a further embodiment, nitrogen gas is used to purge the wet crystals of form 1 using a vacuum to dry them.

[0084] In this invention, unless otherwise defined, the terms "first" or "second" are used to indicate that an element of the method may be added more than once during the method. The first and second elements (e.g., "first cosolvent" and "second cosolvent") may be different or the same. The terms are used to indicate that the element is added a second time during the steps described in this invention.

[0085] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of cefoloza sulfate and a pharmaceutically acceptable carrier, wherein cefoloza sulfate is obtained by a method comprising the steps of: (a) converting cefoloza sulfate DMAc solvate (form 3) to cefoloza sulfate (form 2); (b) forming a cefoloza sulfate solution comprising cefoloza sulfate (form 2); and (c) lyophilizing the cefoloza sulfate solution to obtain a lyophilized cefoloza sulfate composition. In another embodiment, the pharmaceutical composition further comprises tazobactam or a pharmaceutically acceptable salt thereof.

[0086] The term “effective amount” or “therapeutic effective amount” refers to the amount of a subject compound that will elicit a biological or medical response in a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician.

[0087] The pharmaceutical compositions of the present invention may include cefoloza sulfate (form 2) obtained by the methods described herein, in combination with β-lactamase inhibitors such as tazobactam (CAS#: 89786-04-9), avidactam (CAS# 1192500-31-4), sulbactam (CAS# 68373-14-8), and / or clavulanic acid (CAS# 58001-44-8). The β-lactamase inhibitors may be included in crystalline or amorphous forms (such as lyophilized tazobactam or crystalline tazobactam (e.g., U.S. Patents 8,476,425 and 5,763,603) to obtain the pharmaceutical compositions.

[0088] Pharmaceutical compositions comprising cefoloza sulfate (form 2) obtained by the methods of the present invention can be formulated for the treatment of infections by parenteral administration (including subcutaneous, intramuscular, and intravenous). In one specific embodiment, the pharmaceutical compositions described herein are formulated for administration by intravenous injection or infusion. The pharmaceutical antibiotic composition may comprise lyophilized unit dosage forms (e.g., powder in vials) of cefoloza sulfate and a stable amount of sodium chloride (e.g., 125 to 500 mg sodium chloride / 1,000 mg cefoloza active agent). The unit dosage form may be dissolved with a pharmaceutically acceptable carrier and then administered intravenously.

[0089] "Pharmaceutically acceptable carriers" for therapeutic purposes are well-known in the pharmaceutical industry and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro, ed. 1985). For example, sterile saline and phosphate-buffered saline at physiological pH can be used. Preservatives, stabilizers, dyes, and even flavoring agents can be provided in pharmaceutical compositions. For example, esters of sodium benzoate, sorbic acid, and p-hydroxybenzoic acid can be added as preservatives. Ibid., in 1449. Furthermore, antioxidants and suspending agents can be used.

[0090] "Pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention derived from such compounds and an organic or inorganic acid (acid addition salt) or an organic or inorganic base (base addition salt). Examples of pharmaceutically acceptable salts include, but are not limited to, those described, for example, in "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", P. Heinrich Stahl and Camille G. Wermuth (Eds.), published by VHCA (Switzerland) and Wiley-VCH (FRG), 2002. The compounds of the present invention can be used in the form of a free base or a salt (both forms are considered to be within the scope of the present invention).

[0091] In some implementations, the order in which the reactants are added is not important. The reactants can be added together to the solvent (e.g., a single-phase solvent, a two-phase aqueous co-solvent system, etc.) at the same time, or alternatively, some of the reactants can be added separately and some can be added together at different time points.

[0092] Current methods for preparing cefuroxime, as shown below as Method A, involve a three-step purification sequence consisting of column chromatography, nanofiltration, and crystallization to obtain cefuroxime. While the column chromatography and nanofiltration steps yield cefuroxime with high purity, the entire process is time-consuming, has low volumetric efficiency, low yield, and requires specialized manufacturing equipment. Furthermore, the crystallization step is volumetrically inefficient and hampered by slow filtration rates, significantly reducing the productivity of this method.

[0093]

[0094] This invention provides a novel solid form for use in a simplified manufacturing process to produce cefuroxime sulfate (Form 2) of at least the same purity, which can be used as an API in ZERBAXA®. The new manufacturing method, as shown below as Method B, eliminates the existing column chromatography and nanofiltration steps. This method results in higher yields, significantly reduced solvent usage, shorter cycle times, and the use of standard manufacturing equipment. This provides a more productive, environmentally friendly, and convenient manufacturing method. Furthermore, the streamlined purification method reduces overall manufacturing time, ultimately saving costs and reducing energy consumption.

[0095]

[0096] Furthermore, the new manufacturing method (Method B) involves an improved crystallization method for cefoloza sulfate form 1. Compared to Method A, the improved crystallization method results in significantly larger particle growth, which in turn leads to an increased filtration rate. This ultimately reduces manufacturing time, saves costs, and reduces energy consumption.

[0097] Cefoloza sulfate can exist in amorphous solid form, crystalline solid form, or a mixture of solid forms. The crystalline solid form of cefoloza can exist in one or more distinct solid forms, which may additionally contain one or more equivalents of water or solvent (i.e., hydrates or solvates, respectively).

[0098] As described in Example 3, cefuroxime sulfate DMAC solvate (Form 3) can be obtained by forming a cefuroxime slurry comprising cefuroxime salt, a sulfate source, DMAc, water, and a co-solvent, and maintaining the solution under conditions that effectively form a cefuroxime wet cake containing cefuroxime salt in Form 3A. Preferably, the cefuroxime solution is maintained at a temperature that effectively provides the desired purity and yield of solid cefuroxime in Form 3A. The temperature range is from about 5°C to about 20°C. In a further embodiment, the temperature is from about 12°C to about 18°C. Most preferably, it is about 15°C. In addition to temperature, the seed amount (from about 0.05 to about 5.0 w / w%) and the aging time after inoculation (from about 0.5 to about 5.0 hours) are also parameters that can be adjusted to obtain solid cefuroxime in Form 3A. A particularly preferred method for preparing solid form 3A of cefoloza sulfate includes maintaining a water / DMAc / acetonitrile ratio of (1.5-3.5):(0.5-1.5):(1.0-3.0) (v / v / v). More preferably, this ratio is 2.5 water:1.0 DMAc:2.0 acetonitrile (v / v / v). After drying, cefoloza sulfate DMAC solvate form 3A is converted to form 3B.

[0099] The solution containing cefuroxime in form 3 is preferably maintained at a temperature that effectively provides the desired purity and yield of solid cefuroxime in form 1. The temperature is from about 5°C to about 20°C. In a further embodiment, the temperature is from about 10°C to about 14°C. Most preferably, it is about 12°C. In addition to temperature and the amount of strong acid (e.g., sulfuric acid provided in an amount of 0.5 to 2.5 molar equivalents, preferably 1.0 molar equivalents, relative to the molar amount of cefuroxime), the seed amount (e.g., 0.5 to 4.0 w / w%) and the aging time after inoculation (e.g., 1-5 hours) are also parameters that can be adjusted to obtain solid cefuroxime (form 1). A particularly preferred method for preparing solid cefuroxime sulfate (form 1) includes maintaining an acetonitrile / water ratio (v / v) of about 40:60 to about 60:40. More preferably, it is a 50:50 acetonitrile to water ratio (v / v).

[0100] Cefoloza sulfate solid form 2 can be obtained by using cefoloza sulfate DMAc solvate (form 3A or 3B). As described in Example 4, cefoloza sulfate solid form 2 can be synthesized by forming a cefoloza sulfate slurry containing cefoloza sulfate DMAc solvate (form 3A or 3B), acetonitrile, water and antisolvent, maintaining the solution under conditions that effectively form a cefoloza wet cake containing cefoloza sulfate form 1, and then converting cefoloza sulfate form 1 to form 2 after drying.

[0101] The invention is illustrated in the embodiments described below in the general scheme and the subsequent experimental section. This section is set forth to aid in understanding the invention, but is not intended and should not be construed as limiting the invention in any way as set forth in the following claims.

[0102] The compounds of the present invention were prepared by the general methods outlined in the synthetic scheme.

[0103]

[0104]

[0105] Referring to this disclosure, unless otherwise specifically defined, the technical and scientific terms used herein will have the meanings commonly understood by one of ordinary skill in the art.

[0106] Some abbreviations that may be used in this article include:

[0107] Aq. Water-based,

[0108] BOC (Boc) N- tert-butoxycarbonyl,

[0109] C. Celsius

[0110] calc. (calculated)

[0111] CXA cefoloza,

[0112] DMAc N,N-dimethylacetamide,

[0113] DMB 1,3-dimethoxybenzene,

[0114] DMB - Triphenylmethyl 3,3-dimethyl-1-butanol triphenylmethyl

[0115] EDC-HCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,

[0116] equiv. equivalent (of quantities).

[0117] Et3N triethylamine,

[0118] h hours (various hours)

[0119] HPLC (High Performance Liquid Chromatography)

[0120] IPA isopropyl alcohol; isopropyl alcohol,

[0121] KTFA potassium trifluoroacetate,

[0122] MeCN acetonitrile,

[0123] MS mass spectrometry,

[0124] MTBE (methyl tert-butyl ether)

[0125] Pd2dba3 tris(dibenzylacetone)dipalladium(0),

[0126] PIX potassium isopropyl xanthate,

[0127] PMB 4-methoxybenzyl ether,

[0128] ppm (parts per million)

[0129] rt (or rt or RT) room temperature,

[0130] SIX sodium isopropyl xanthate,

[0131] tert -Bu tert-butyl,

[0132] TATD ( Z )-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropyl-2-yl)oxy)imino)acetic acid,

[0133] TATD-CLE (6 R 7 R )-7-(( Z )-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropyl-2-yl)oxy)imino)acetamyl)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (4-methoxybenzyl) ester,

[0134] TDAPP tris(4-(dimethylamino)phenyl)phosphite,

[0135] TEA triethylamine,

[0136] TFA (trifluoroacetic acid)

[0137] THF tetrahydrofuran,

[0138] TLC (Thin Layer Chromatography)

[0139] UBT (2-(3-(1-methyl-5-(triphenylmethylamino)-1 H -pyrazol-4-yl)ureoyl)ethyl)tert-butyl carbamate.

[0140] Experimental details

[0141] X-ray powder diffraction (XRPD)

[0142] Powder X-ray diffraction data were acquired on a Panalytical X-pert Pro PW3040 system configured in a Bragg-Brentano configuration and equipped with a Cu radiation source for Kα monochromaticization using a nickel filter. A fixed slit optics configuration was used for data acquisition. Data were acquired between 2° and 40° 2θ. Samples were prepared by gently pressing a wet solid sample or a dry powder sample of form 3 onto a shallow cavity zero-background silicon holder. The holder was covered with a Kapton film. Figure 3 and 4 The pattern shown has undergone background correction. The results are shown in [link to documentation]. Figure 3 and 4 middle.

[0143] Thermal analysis

[0144] (TGA): Thermogravimetric analysis was performed on a Perkin-Elmer TGA-7 thermogravimetric analyzer. Aliquots (~8 mg) of the dried form 3 powder were heated from 25 °C to 240 °C at 5 °C / min, while being purged with nitrogen at 50 mL / min in an open pan. Results are shown in […]. Figure 1 middle.

[0145] (DSC): A TA Instruments 2920 differential scanning calorimeter was used to monitor thermal events as a function of temperature rise. Aliquots (~5.5 mg) of dried form 3 powder were heated from 25 °C to 240 °C at 5 °C / min, while being purged with nitrogen at 50 mL / min in an aluminum-capped pan. Results are shown in […]. Figure 2 middle.

[0146] Example 1

[0147]

[0148] The method for preparing starting materials to prepare cefoloza is shown in Figure 6A and Figure 6BIt is described in U.S. Patent Nos. 7,129,232 and 7,192,943, and in Toda et al., "Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205," Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008).

[0149] TATD (70 g, 99 wt%) and 1.0 equivalent of ACLE-HCl (86.09 g, 89.6 wt% free base) were dissolved in 525 mL of acetonitrile at -10 °C. Pyridine (19.91 g) was added, followed by 3 parts of 1.2 equivalent of EDC∙HCl (48.26 g). The resulting reaction mixture was aged at -10 °C for 3 hours. The reaction mixture was then quenched with 350 mL of toluene and 315 mL of 0.5 M sulfuric acid solution while maintaining an internal temperature below -8 °C. The biphase mixture was warmed to 20–25 °C, aged for 15 minutes, and then allowed to settle to obtain two layers. The organic layer was separated and placed in 315 mL of 0.5 M sulfuric acid solution while maintaining an internal temperature below 25 °C. The biphase mixture was aged at 25 °C for 15 minutes and then allowed to settle to obtain two layers. The organic layer was separated and loaded into 140 mL of 10 wt% sodium chloride solution, and the resulting mixture was aged at 30 °C for 15 min. The two-phase mixture was then allowed to settle to obtain two layers. The resulting organic layer was separated and loaded into 140 mL of 10 wt% sodium chloride solution. The reaction mixture was stirred at 30 °C for 15 min, and then allowed to settle to obtain two layers. The final organic layer was separated and concentrated to a volume of 455 mL. The batch was cooled to 20 °C and seeded. The resulting slurry was aged at 20 °C for 2 h. After 8 h, 959 mL of toluene was added to the slurry, and then aged at 20 °C for 2 h. The crystals were collected, washed with 210 mL of 5 vol% ACN in toluene solution, followed by washing with 560 mL of toluene. The filter cake was dried under vacuum at 25 °C under nitrogen purging for 17 h to obtain TATD-CLE.

[0150] Example 2

[0151]

[0152] TATD-CLE (70.59 g, at 85 wt%), UBT (54.77 g), KTFA (20.51 g), TDAPP (3.10 g), and 570 mL THF were charged into a reactor. Pd2dba3 (0.832 g) was added to the reaction mixture and the mixture was stirred at 15 °C for 15 hours. The resulting reaction mixture was quenched with thioglycerol (0.962 g) and concentrated to a volume of 300 mL. A constant volume of 300 mL was maintained by solvent-switching with 540 mL EtOAc at a constant rate during distillation to remove THF. After solvent-switching, EtOAc (450 mL), solka floc (3 g), and 20 wt% sodium chloride solution (180 mL) were added, and the reaction mixture was stirred at 15 °C for 30 minutes. The resulting batch was filtered, and the organic layer was separated. Add 5 wt% NaHSO4 solution (180 mL) and stir the extraction mixture at 15 °C for 30 min. Allow the two-phase mixture to settle to obtain two layers. Separate the organic layer, load it with Aquaguard (4.5 g), and stir at 15 °C for 2 h. Then filter the slurry to remove carbon and concentrate to a volume of 300 mL. Add DMB (156 mL) and concentrate the batch to a volume of 300 mL. Add TFA (416 mL) over 1 h and stir the resulting reaction mixture at 20 °C for 3 h. Cool the reaction mixture to 5 °C and load it with 834 mL MTBE to obtain a light brown slurry. Warm the resulting slurry to 20 °C. Collect the solids, wash three times with MTBE (312 mL), and dry under vacuum with nitrogen for 17 h to obtain 94.5 g cefuroxime-TFA (CXA-TFA).

[0153] Example 3

[0154] Preparation of cefoloza sulfate DMAc solvate (form 3).

[0155]

[0156] Cefoloza-TFA (14.3 g, 56 wt%) and 48 mL of 2.5:1:2 water:DMAc:acetonitrile v:v:v (50:19:31 w / w) were combined and stirred at 15 °C to obtain a slurry. Potassium isopropyl xanthate (PIX) (0.104 g, 5 mol%) was added in one part, and the resulting slurry was stirred at 15 °C for 30 min. A second part of potassium isopropyl xanthate (0.104 g, 5 mol%) was added, and the reaction mixture was stirred at 15 °C for 30 min. Iodine (0.076 g, 2.5 mol%) was then added, and the slurry was stirred at 15 °C for 1 h. The slurry was then filtered, and the resulting waste cake was washed with 8 mL of 2.5:1:2 water:DMAc:acetonitrile. The filtrate and washings were combined and cooled to 15 °C. Ammonium bisulfate (1.449 g, 1.05 equivalents) was added and stirred at 15 °C for 15 min. Acetonitrile (12 mL) was added, followed by cefoloza sulfate DMAc solvate (form 3) (0.08 g). The resulting slurry was aged at 15 °C for 3 h. After 10 h, acetonitrile (100 mL) was added and the resulting slurry was aged at 15 °C for 1 h. The solid was filtered, washed with water:DMAc:acetonitrile (2.5:1:13), then washed with acetonitrile, and then dried under vacuum with nitrogen at 25 °C for 17 h to give cefoloza sulfate DMAc solvate (form 3B) (9.51 g, 89% yield).

[0157] The X-ray powder diffraction pattern of crystalline cefoloza sulfate form 3A (wet phase) is depicted on... Figure 3 The relevant data is summarized in Table 1.

[0158] Table 1: X-ray powder diffraction pattern of cefoloza sulfate form 3A

[0159] (Wet phase) pattern

[0160]

[0161] The X-ray powder diffraction pattern of crystalline cefuroxime sulfate form 3B (dry phase) is depicted on Figure 4 The relevant data is summarized in Table 2.

[0162] Table 2: X-ray powder diffraction pattern of cefoloza sulfate form 3B

[0163] (Dry phase) pattern

[0164]

[0165] Example 4

[0166] Preparation of cefoloza sulfate (form 2).

[0167]

[0168] Cefoloza sulfate DMAc solvate (50 g, 70.4 wt%) was dissolved in 317 mL of 1:1 acetonitrile:water (v:v) at 20 °C. The batch was cooled to 15 °C and then 50 wt% sulfuric acid (10.3 g, 1.0 equivalent) was added. The internal temperature was maintained between 15 and 20 °C (pH = 0.1 to 1.0). The resulting solution was filtered through a 0.22 μm filter and then cooled to 12 °C. Cefoloza sulfate (slurry of form 2 or form 1) (0.35 g) was added to the reaction mixture, and the resulting slurry was aged at 12 °C for 3 hours to obtain a seed bed. Acetonitrile (405 mL) was added via a syringe pump at 12 °C over 10 hours, and then the mixture was aged for 1 hour. Triethylamine (TEA) (5.33 g, 1.0 equivalent, 7.35 mL) was added to adjust the pH (1.5 to 3) and the resulting slurry was aged for 3 hours. The solids were filtered, washed with acetonitrile:water (4:1), and then washed with acetone to give cefoloza sulfate (form 1), which was then dried under vacuum at 25°C for 17 hours after being purged with nitrogen to give cefoloza sulfate (form 2) (39.3 g, 95% yield).

[0169] Example 5

[0170] Crystallization method for preparing cefoloza sulfate form 1: slurry filtration characterization

[0171] Laboratory filtration measurements were performed on slurries crystallized from an IPA / water system (as described in U.S. Patent 7,129,232) and from an acetonitrile / water system. Approximately 30 g of form I-hydrate was crystallized in each solvent system prior to filtration characterization. Rosemund filters were used with Kavon 909 cloth (5 μm porosity) as the filter medium. Compressed nitrogen was used as the pressure source. The mass of the filtrate was collected as a function of time using a balance connected to a computer with 1 Hz data acquisition. The pressure in the acetonitrile / water system varied from 10–40 psig during the experiments, and the pressure in the IPA / water system varied from 10–60 psig during the experiments. Figure 5 Describes the weight of the filtrate as a function of time during pressure filtration of slurries prepared from 2-propanol / water and acetonitrile / water. (e.g.) Figure 5As shown, for an equal amount of Form 1 crystals (~30 g), the Form 1 material prepared from acetonitrile / water (crystallized from dissolved Form 3) has a significantly shorter filtration time (~0.8 h) than the Form 1 material prepared from 2-propanol / water (~14 h for filtration). The shorter filtration time of the material crystallized from acetonitrile / water compared to 2-propanol / water is due to the larger particles prepared from acetonitrile / water and due to the increased slurry density from acetonitrile / water (i.e., less filtrate to remove from the slurry prepared from acetonitrile / water compared to IPA / water).

[0172] As described herein, forms 3A and / or 3B can be dissolved in acetonitrile:water under acidic conditions and crystallized from acetonitrile:water to produce form 1. Upon drying, form 1 is converted to form 2. This novel crystallization method for forming cefuroxime sulfate form 1 from acetonitrile / water under acidic conditions yields significantly larger particles. This novel crystallization method is also a method with higher volumetric productivity (~2X improvement) compared to the existing method (Method A). The method of the present invention using acetonitrile / water crystallization produces significantly larger particles than the 2-propanol (IPA) / water method. Due to the larger particles and higher volumetric efficiency, this method has a significantly faster filtration rate when compared to form 1 crystals prepared from IPA / water. The improved volumetric productivity and faster filtration rate of form 1 crystals prepared from acetonitrile / water result in improved production capacity.

Claims

1. Solid form of cefoloza sulfate DMAc solvate, which produces X-ray powder diffraction (XRPD) patterns with diffraction at angles (2θ ± 0.2) of 12.8, 17.5, 21.7, 24.0 and 24.

6.

2. The solid form of cefoloza sulfate DMAc solvate of claim 1, which produces X-ray powder diffraction (XRPD) patterns with additional diffraction at angles (2θ ± 0.2) of 9.4, 18.9, 24.0, 25.7 and 26.

9.

3. The solid form of cefoloza sulfate DMAc solvate, which produces X-ray powder diffraction (XRPD) patterns with diffraction at angles of 11.0, 21.0, 22.5 and 24.0 (2θ ± 0.2).

4. A method for preparing the solid form of cefoloza sulfate DMAc solvate of claim 1, comprising the following steps: a) Cefoloza TFA, water, DMAc and a first cosolvent are combined to form a slurry, and iodine and xanthate are added to the slurry; b) Filter the slurry to produce filtrate; c) Combine the filtrate and sulfate source; d) Add a second cosolvent and DMAc to solvate the seed to produce the product; and e) Filter the product to obtain a wet solid of cefoloza sulfate DMAc solvate. The first and second cosolvents are independently selected from acetonitrile, isopropanol, tert-amyl alcohol, 1-propanol, ethanol, tert-butanol, dioxane, and THF, and the xanthate is potassium isopropyl xanthate, sodium isopropyl xanthate, potassium ethyl xanthate, sodium ethyl xanthate, potassium tert-butyl xanthate, or sodium tert-butyl xanthate.

5. The method of claim 4, wherein the first cosolvent and the second cosolvent are independently selected from acetonitrile, isopropanol, and tert-amyl alcohol.

6. The method according to claim 5, wherein both the first cosolvent and the second cosolvent are acetonitrile.

7. The method according to claim 4, wherein the sulfate source is selected from ammonium bisulfate, ammonium sulfate, sodium bisulfate, potassium bisulfate, lithium bisulfate and tetrabutylammonium bisulfate.

8. A method for preparing the solid form of cefoloza sulfate DMAc solvate of claim 3, comprising the following steps: a) Cefoloza TFA, water, DMAc and a first cosolvent are combined to form a slurry, and iodine and xanthate are added to the slurry; b) Filter the slurry to produce filtrate; c) Combine the filtrate and sulfate source; d) Add a second cosolvent and DMAc to solvate the seed to produce the product; e) Filter the product to obtain a wet solid of cefoloza sulfate DMAc solvate, and f) Dry the cefoloza sulfate DMAc solvate to produce a dry solid of cefoloza sulfate DMAc solvate. The first and second cosolvents are independently selected from acetonitrile, isopropanol, tert-amyl alcohol, 1-propanol, ethanol, tert-butanol, dioxane, and THF, and the xanthate is potassium isopropyl xanthate, sodium isopropyl xanthate, potassium ethyl xanthate, sodium ethyl xanthate, potassium tert-butyl xanthate, or sodium tert-butyl xanthate.

9. The method of claim 8, wherein the xanthate is potassium isopropyl xanthate.

10. A method for preparing cefoloza sulfate in solid form, comprising the following steps: a) Combining the cefoloza sulfate DMAc solvate of claim 1 or 3, acetonitrile, and water to produce a solution; b) Add sulfuric acid to the solution; c) Filter the solution and add cefoloza sulfate seed crystals to produce a slurry; d) Add an antisolvent to the slurry, wherein the antisolvent is selected from acetonitrile, isopropanol, tert-amyl alcohol, 1-propanol, ethanol, tert-butanol, dioxane, methyl tert-butyl ether (MTBE) and THF; e) Add alkali to the slurry to adjust the pH; f) The slurry is filtered and washed with a solvent mixture to produce wet crystals of cefoloza sulfate; and g) Dry the wet crystals of cefuroxime sulfate to produce the solid form of cefuroxime sulfate.

11. The method of claim 10, wherein the antisolvent is selected from acetonitrile.

12. The method according to claim 10, wherein the base in step e) is trimethylamine.

13. The method of claim 10, wherein the solvent mixture in step f) is a mixture of water and acetonitrile.

14. The method of claim 10, wherein the wet crystals of cefoloza sulfate are washed with acetone before drying in step g).

15. A method for preparing a pharmaceutical composition comprising combining a therapeutically effective amount of cefoloza sulfate and a pharmaceutically acceptable carrier, wherein cefoloza sulfate is obtained by a method comprising the step of: (a) preparing a solid form of cefoloza sulfate by the method of claim 10; (b) Forming a cefoloza sulfate solution containing cefoloza sulfate, and (c) The cefoloza sulfate solution was freeze-dried to obtain a freeze-dried cefoloza sulfate composition.

16. The method of claim 15, wherein the pharmaceutical composition further comprises tazobactam or a pharmaceutically acceptable salt thereof.

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