EA042386B1 - CRYSTALLINE FORMS OF TEBIPENEM PIVOXIL, COMPOSITIONS CONTAINING THEM, METHODS OF MANUFACTURING AND METHODS OF APPLICATION - Google Patents

Description

Cross-reference to related application

This application claims priority under a provisional patent application

US No. 62/455109, filed February 6, 2017, which is incorporated herein by reference in its entirety.

Field of invention

Disclosed are solid salt forms of tebipenem pivoxil, including crystalline forms, pharmaceutical compositions and preparations containing solid salt forms of tebipenem pivoxil, methods for using the crystalline forms to treat bacterial infections, and methods for making the crystalline forms.

Prior Art

Molecules in a crystalline solid are arranged in a crystal lattice, which is a three-dimensional structure in which structural elements (unit cells) are repeated in a constant manner. Different crystalline forms of the same substance (polymorphs) have different crystal lattices, which can lead to important differences in their properties, uses, and industrial value. For example, graphite and diamond are polymorphs of crystalline carbon. Pharmaceutical compound polymorphs may also differ distinctly, if not substantially, in their properties, including properties relevant to the formulation of such pharmaceutical compounds and the development of solid dosage forms such as tablets and capsules containing such formulations. The crystalline form of the medicinal product must also comply with regulatory requirements regarding its manufacture.

Tebipenem pivoxil is a carbapenem antibiotic useful in the treatment of antibiotic-resistant bacterial infections. New solid forms such as crystalline salt forms are needed to improve the therapeutic use of tebipenem pivoxil.

Short description

This document discloses crystalline salt forms of tebipenem pivoxil. These crystalline forms include tebipenem pivoxil ethanesulfonate crystalline salt form (Form A), tebipenem pivoxil ketoglutarate crystalline salt form (Form A), tebipenem pivoxil maleate salt forms (Form A and Form B), tebipenem pivoxil malate salt form (Form A), tebipenem pivoxil methanesulfonate form (Form B), tebipenem pivoxil hydrobromide salt form (Form B), and tebipenem pivoxil edisylate salt form (Form A).

Also disclosed herein is a composition comprising a crystalline salt of tebipenem pivoxil and a pharmaceutically acceptable carrier.

Also disclosed herein is a method of treating an antibiotic-resistant bacterial infection, comprising administering to a patient in need of such treatment a therapeutically effective amount of tebipenem pivoxil crystalline salt.

Also included are methods for making crystalline salt forms of tebipenem pivoxil.

Brief description of graphic materials

The above and other aspects, advantages and features of the present invention will become more apparent by a more detailed description of its typical embodiments with reference to the accompanying figures.

Fig. 1. XRPD diffraction pattern of tebipenem pivoxil ethanesulfonate form A.

Fig. 2. DSC and TGA profiles of tebipenem pivoxil ethanesulfonate ethanesulfonate form A.

Fig. 3. XRPD diffraction pattern of the crystalline salt form A of tebipenem pivoxil ketoglutarate.

Fig. 4. DSC and TGA profiles of the crystalline salt form A of tebipenem pivoxil ketoglutarate.

Fig. 5. XRPD pattern of the crystalline salt Form A of tebipenem pivoxil maleate.

Fig. 6. DSC and TGA profiles of the crystalline salt form A of tebipenem pivoxil maleate.

Fig. 7. XRPD pattern of the crystalline salt Form B of tebipenem pivoxil maleate.

Fig. 8. DSC and TGA profiles of the crystalline salt Form B of tebipenem pivoxil maleate.

Fig. 9. XRPD diffraction pattern of crystalline tebipenem pivoxil malate salt form A prepared by method 1 in which tebipenem pivoxil is dissolved in MeCN.

Fig. 10. XRPD pattern of crystalline tebipenem pivoxil malate salt form A prepared by method 2, in which tebipenem pivoxil is dissolved in MeCN.

Fig. 11. DSC and TGA profiles of tebipenem pivoxil malate crystalline salt form A prepared by method 1.

Fig. 12. XRPD pattern of the crystalline salt Form B of tebipenem pivoxil methanesulfonate.

Fig. 13. DSC and TGA profiles of the crystalline salt Form B of tebipenem pivoxil methanesulfonate.

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Fig. 14. XRPD pattern of the crystalline salt form B of tebipenem pivoxil hydrobromide.

Fig. 15. DSC and TGA profiles of the crystalline salt Form B of tebipenem pivoxil hydrobromide.

Fig. 16. XRPD pattern of the crystalline salt form A of tebipenem pivoxil edisylate.

Fig. 17. DSC and TGA profiles of the crystalline salt form A of tebipenem pivoxil edisylate.

Fig. 18. XRPD pattern of tebipenem pivoxil crystalline free base.

Fi. 19. XRPD pattern of the crystalline salt form A of tebipenem pivoxil hydrochloride.

Fig. 20. DSC and TGA profiles of tebipenem pivoxil hydrochloride salt Form A.

Fig. 21. XRPD pattern of the crystalline salt Form C of tebipenem pivoxil hydrobromide.

Fig. 22. DSC and TGA profiles of the crystalline salt form C of tebipenem pivoxil hydrobromide.

Fig. 23. XRPD pattern of the crystalline salt form D of tebipenem pivoxil hydrobromide.

Fig. 24. DSC and TGA profiles of the crystalline salt form D of tebipenem pivoxil hydrobromide.

Fig. 25. XRPD pattern of the crystalline B+C salt form of tebipenem pivoxil methanesulfonate.

Fig. 26. DSC and TGA profiles of the crystalline salt form B+C of tebipenem pivoxil methanesulfonate.

Fig. 27. XRPD pattern of the crystalline salt form D of tebipenem pivoxil methanesulfonate.

Fig. 28. DSC and TGA profiles of the crystalline salt form D + form B of tebipenem pivoxil methanesulfonate.

Detailed description

The present invention will now be described in more detail with reference to the accompanying figures. However, the present invention may be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided in order for this disclosure to be complete and complete, and to fully convey the scope of the present invention to those skilled in the art. Throughout the description, like reference numerals refer to like elements.

Terminology/

Dosage form means the unit of administration of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalation forms, transdermal forms, and the like.

Pharmaceutical compositions are compositions containing at least one active agent, for example, the crystalline salt of tebipenem pivoxil, and at least one other substance, such as a carrier, excipient or diluent. The pharmaceutical compositions comply with the GMP (Good Manufacturing Practice) standards of the US Food and Drug Administration for medicinal products for human or non-human medicinal products.

The term carrier, as applied to the pharmaceutical compositions described herein, refers to the diluent, excipient, or carrier vehicle with which the active compound is provided.

Pharmaceutically acceptable excipient means an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as for pharmaceutical use in humans. A pharmaceutically acceptable excipient as used herein includes one or more such excipients.

The patient is a non-human human or animal in need of medical treatment. Medical treatment may include treatment of an existing condition such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In some embodiments, the patient is a human.

Providing means prescribing for receiving, introducing, selling, distributing, transporting (for profit or not), making, preparing or distributing.

Providing a crystalline salt form of tebipenem pivoksil with at least one additional active agent means that the crystalline salt form of tebipenem pivoksil and the additional active agent(s) are provided simultaneously in one dosage form, are provided concurrently in separate dosage forms or provided in separate dosage forms for administration separated by a certain amount of time, ie within the time that both tebipenem pivoxil and at least one additional active agent are in the patient's bloodstream. The crystalline salt form of tebipenem pivoxil and the co-active agent should not be administered to a patient by the same healthcare professional. The additional active agent or agents do not necessarily require a prescription. Administration of the tebipenem pivoxil crystalline salt form or at least one additional active agent may be by any suitable route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories, or topical contact.

Treatment as used herein includes providing a crystalline salt form of tebipenem pivoxil and at least one additional active agent sufficient to (a) reduce the likelihood of a disease or symptom of a disease in a patient who is predisposed to the disease but who has not yet been diagnosed as having it (for example, preventing a bacterial infection in a patient traveling to an area where the risk of exposure to a bacterial infection is high); (b) disease suppression, ie. delays in its development; and (c) relieving the condition of the disease, i. e. ensure disease regression. Treating and treating also means providing a therapeutically effective amount of the crystalline salt form of tebipenem pivoxil and at least one additional active agent to a patient having a microbial infection or susceptible to a microbial infection, such as an antibiotic-resistant bacterial infection or an infection caused by gram-negative bacteria.

A therapeutically effective amount of a pharmaceutical combination of the present invention means an amount effective, when administered to a patient, to provide a therapeutic benefit such as symptomatic relief, eg an amount effective to reduce the symptoms of a bacterial infection. For example, a patient infected with a bacterial infection may show abnormal levels of some hemocytes, particularly leukocytes (white blood cells), such as an increase in the number of neutrophils and a decrease in the number of lymphocytes. A therapeutically effective amount, therefore, is an amount sufficient to cause the leukocyte level to return to the normal range. A therapeutically effective amount is also an amount sufficient to prevent a significant increase or a significant decrease in the detectable level of bacteria or antibacterial antibodies in the patient's blood, serum or tissues.

The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ^nC , ^13C , and ^14C .

It will be understood that when an element is referred to under another element, it may be directly under the other element, or intermediate elements may be present between them. In contrast, when an element immediately adjacent to another element is referred to, no intermediate elements are present.

It will be understood that although the terms first, second, third, and so forth may be used herein to describe various elements, components, ranges, layers, and/or parts, these elements, components, ranges, layers, and/or parts should not be limited to these terms. . These terms are only used to distinguish one element, component, range, layer, or part from another element, component, range, layer, or part. Thus, the first element, component, range, layer, or part discussed below may be referred to as the second element, component, range, layer, or part without deviating from the principles of the present invention herein.

The terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. As used herein, the singular is intended to include the plural, including at least one, unless the context clearly indicates otherwise. Or means and/or. As used herein, the term and/or includes any and all combinations of one or more of the related items listed. It will also be understood that the terms contains and/or comprising, or includes and/or including when used in this description, define the presence of the specified features, ranges, integers, steps, operations, elements and/or components, but do not exclude the presence or addition one or more other features, ranges, integers, steps, operations, elements, components, and/or groups thereof.

Unless otherwise defined, all terms (including technical and scientific terms) used in this document have the same meaning as commonly understood by a person skilled in the art to which this invention pertains. It will also be understood that terms, such as those defined in commonly used dictionaries, are to be understood as having a meaning that is consistent with their meaning in the context of the related art and the present invention, and will not be understood in an idealized or overly formal sense unless it is not explicitly defined in this document.

Tebipenem pivoxil (CAS registration number 161715-24-8) has the following structure (1)

Disclosed herein are crystalline salt forms of tebipenem pivoxil ethanesulfonate salt form (Form A), tebipenem pivoxil ketoglutarate crystalline salt form (Form A), tebipenem pivoxil maleate salt forms (Form A and Form B), tebipenem pivoxil malate salt form (Form A) , the salt form of tebipenem pivoxil methanesulfonate (form B) and the salt form of tebipenem pivoxil hydrobromide (form B).

Tebipenem pivoxil salt crystalline forms include single and multi-component crystalline forms, including, without limitation, polymorphs, solvates, hydrates, co-crystals, and clathrates. Some embodiments herein provide single component crystalline forms of the tebipenem pivoxil salt. Other embodiments herein provide multicomponent crystalline forms containing the tebipenem pivoxil salt. The multicomponent crystalline forms provided herein include crystalline forms that may be described by the terms salt, co-crystal, hydrate, solvate, clathrate, and/or polymorph, and include crystalline forms that may be described by one or more of these terms.

Crystalline forms containing the tebipenem pivoxil salt can be prepared by the methods described herein, including the methods described in the examples below, or by methods known in the art, including heating, cooling, freeze drying, lyophilization, flash cooling of the melt, flash evaporation solvent, slow evaporation of the solvent, recrystallization from a solvent, addition of an anti-solvent, recrystallization from a suspension, crystallization from a melt, desolvation, recrystallization in a confined space, such as, for example, in nanopores or capillaries, recrystallization on surfaces or matrices, such as, for example, on polymers, recrystallization in the presence of additives such as, for example, co-crystal countermolecules, desolvation, dehydration, rapid cooling, slow cooling, exposure to solvent and/or water, drying, including, for example, vacuum drying, vapor phase diffusion, sublimation, milling ( including e.g., cryo-grinding, solvent-drop milling, or liquid-assisted milling), microwave-induced precipitation, ultrasonic-induced precipitation, laser-induced precipitation, and supercritical fluid precipitation. The particle size of the resulting crystalline forms, which may vary (for example, from nanometer sizes to millimeter sizes), can be controlled, for example, by changing the crystallization conditions, such as, for example, the crystallization rate and/or the crystallization solvent system, or by particle size reduction techniques. such as grinding, grinding, micronization or sonication.

Without wishing to be bound by any particular theory, certain crystalline forms have physical properties such as stability, solubility and dissolution rate suitable for pharmaceutical and therapeutic dosage forms. In addition, while not wishing to be bound by any particular theory, certain crystalline forms are characterized by physical properties (e.g., density, compressibility, hardness, structure, cleavage, cohesion, solubility, water absorption, electrical properties, thermal behavior, solid reactivity). condition, physical stability, and chemical stability) that affect specific processes (e.g., yield, filtration, washing, drying, milling, mixing, tabletting, flow, dissolution, formulation, and lyophilization) that make certain crystalline forms suitable for solid drug formulation. forms. Such properties can be determined using specific analytical chemistry techniques, including solid phase analytical techniques (eg, x-ray diffraction, microscopy, spectroscopy, and thermal analysis) as described herein and known in the art.

Some embodiments herein provide compositions containing one or more crystalline forms. Other embodiments provide compositions of one or more crystalline forms in combination with other active ingredients. Some embodiments provide methods for using these compositions in the treatment, prevention, or control of diseases and disorders, including, without limitation, the diseases and disorders described herein.

In addition to crystal forms containing the tebipenem pivoxil salt, crystal forms containing tebipenem pivoxil salt prodrugs are contemplated herein.

The crystalline forms provided herein may also include non-natural atomic isotope ratios of one or more atoms in the tebipenem pivoxil salt. For example, the compound may be labeled with radioactive isotopes such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), sulfur-35 ( ³⁵ S) or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic agents, eg, antibacterial therapeutic agents, research reagents, eg, binding assay reagents, and diagnostic agents, eg, in vivo imaging agents. All isotopic variants of the tebipenem pivoxil salt, radioactive or not, are encompassed by the scope of the embodiments presented herein.

The present invention includes a crystalline salt form of tebipenem pivoxil ethanesulfonate, wherein the XRPD of the Cu Ka source form contains characteristic data at the 2θ angle values shown in FIG. 1 (form A).

The present invention includes a crystalline salt form of tebipenem pivoxil ethanesulfonate (Form A) wherein the XRPD of the form prepared using a Cu Ka source has any 5, 6, 7, 8, 9, 10, 11, 12 or more characteristic 2θ values: 5 .7, 8.8, 9.6, 10.8, 12.4, 13.7, 15.1, 16.9, 17.8, 18.4, 18.7, 19.0, 19.3 , 20.0, 20.3, 21.0, 21.8, 22.1, 22.4, 23.0, 23.4, 24.9, 25.2, 25.9, 26.2, 26 .5, 26.8, 27.2, 27.9, 28.6, 29.2, and 29.7+/-0.2 degrees 2θ.

The present invention includes a crystalline salt form of tebipenem pivoxil ethanesulfonate having an XRPD pattern obtained using a Cu Ka source that contains peaks at 2θ angles of 9.6, 12.4, 15.1, 19.0, and 20.3+/- 0.2 degrees 2θ or 10.8, 13.7, 15.9, 22.1 and 27.9+/-0.2 degrees 2θ.

The present invention includes a crystalline salt form of tebipenem pivoxil ethanesulfonate Form A further characterized by the DSC profile essentially shown in FIG. 2.

The crystalline salt form of tebipenem pivoxil ethanesulfonate Form A further has a DSC profile characterized by an endotherm with an onset at 70.8°C and a minimum at 90.7°C.

The present invention includes a crystalline salt form of tebipenem pivoxil ketoglutarate (Form A) wherein the XRPD of the form prepared using a Cu Ka source contains characteristic data at the 2θ angle values shown in FIG. 3.

The present invention includes a crystalline salt form of tebipenem pivoxil ketoglutarate (Form A) wherein any 5, 6, 7, 8, 9, 10, 11, 12 or more of the following values on the XRPD of the Cu Ka source form: 5, 4, 8.6, 9.8, 10.4, 10.7, 12.7, 13.2, 13.5, 14.0, 16.2, 17.0, 17.2, 17.7, 18.0, 18.7, 18.9, 19.4, 19.6, 20.0, 20.7, 21.1, 21.6, 21.8, 22.7, 23.0, 23, 6, 24.6, 26.7, 27.1, 27.4, 28.3, 28.7 or 29.6.

The present invention includes a crystalline salt form of tebipenem pivoxil ketoglutarate (form A, characterized by an XRPD pattern obtained using a Cu Ka source, which contains peaks at 2θ angle values of 8.6, 10.7, 13.2, 16.2 and 17.2 +/-0.2 degrees 2θ or 9.8, 12.7, 13.5, 17 and 17.7+/-0.2 degrees 2θ.

The crystalline salt form of tebipenem pivoxil ketoglutarate Form A further exhibits a DSC profile essentially shown in FIG. 4.

The crystalline salt form of tebipenem pivoxil ketoglutarate, form A, is further characterized by a DSC profile characterized by an endotherm with an onset at 36.6°C and a minimum at 57.0°C and a second endotherm with an onset at 106.5°C and a minimum at 117°C .

The present invention includes a crystalline salt form of tebipenem pivoxil maleate wherein the XRPD of the Cu Ka source form contains characteristic data at the 2θ angle values shown in FIG. 5 (form A).

The present invention includes a crystalline salt form of tebipenem pivoxil maleate (Form A) wherein any 5, 6, 7, 8, 9, 10, 11, 12 or more of the following values on the XRPD of the Cu Ka source form: 8, 0, 8.6, 10.8, 11.2, 11.9, 12.2, 12.6, 15.0, 15.4, 15.7, 16.9, 18.2, 18.7, 19.4, 19.9, 20.4, 21.2, 22.5, 23.1, 24.2, 24.8, 25.7, 26.5, 27.5 or 28.3.

The present invention includes a crystalline salt form of tebipenem pivoxil maleate (form A0 characterized by an XRPD pattern obtained using a Cu Ka source, which contains peaks at 2θ angle values of 8, 12.6, 15.4, 16.0 and 18.7+/ -0.2 degrees 2θ or 8.6, 15.0, 15.7, 19.4 and 19.9+/-0.2 degrees 2θ.

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The present invention includes tebipenem pivoxil maleate crystalline salt Form A further characterized by the DSC profile essentially shown in FIG. 6.

The present invention includes tebipenem pivoxil maleate crystalline salt form A further characterized by a DSC profile characterized by an endotherm with onset at 50.6°C and a minimum at 74.3°C and a second endotherm with onset at 103.0°C and minimum at 110. 1°C.

The present invention includes a crystalline salt form of tebipenem pivoxil maleate wherein the XRPD of the Cu Ka source form contains characteristic data at the 2θ angle values shown in FIG. 7 (form B).

The present invention includes a crystalline salt form of tebipenem pivoxil maleate (Form B) wherein, on the XRPD of the form prepared using a Cu Ka source, are any 5, 6, 7, 8, 9, 10, 11, 12 or more of the following: 5, 5, 8.9, 10.1, 10.6, 11.0, 12.8, 13.6, 14.3, 14.9, 16.7, 17.0, 17.2, 17.9, 18.6, 19.0, 19.4, 20.2, 20.5, 20.8, 21.4, 21.9, 22.2, 23.1, 24.0, 24.5, 25, 1, 25.5, 26.2, 27.5, 28.1, 28.9 or 29.6.

The present invention includes a crystalline salt form of tebipenem pivoxil maleate (Form B) characterized by an XRPD pattern obtained using a Cu Ka source that contains peaks at 2θ angle values of 8.9, 13.6, 17.0, 18.6 and 20, 8+/-0.2 degrees 2θ or 11.0, 14.3, 19.0, 20.2 and 21.4+/-0.2 degrees 2θ.

The present invention includes a crystalline salt form (Form B) of tebipenem pivoxil maleate further characterized by the DSC profile essentially shown in FIG. 8.

The present invention includes a crystalline salt Form B of tebipenem pivoxil maleate further characterized by a DSC profile characterized by an endotherm with an onset at 40.3°C and a minimum at 65.3°C and a second endotherm with an onset at 114.7°C and a minimum at 119 6°C.

The present invention includes a crystalline salt form of tebipenem pivoxil malate, wherein the XRPD of the form prepared using a Cu Ka source contains characteristic data at the 2θ angle values shown in FIG. 9 (form A).

The present invention includes a crystalline salt form of tebipenem pivoxil malate (Form A) wherein any 5, 6, 7, 8, 9, 10, 11, 12 or more of the following values on the XRPD of the Cu Ka source form: 9, 1, 9.3, 11.0, 11.8, 12.3, 12.9, 13.1, 14.4, 14.9, 15.3, 16.0, 16.6, 17.6, 18.5, 19.0, 19.9, 20.5, 20.8, 21.4, 21.9, 22.2, 23.1, 23.4, 23.9, 24.8, 25, 5, 26.0, 26.3, 27.7 or 28.4.

The present invention includes a crystalline salt form of tebipenem pivoxil malate (form A) characterized by an XRPD pattern obtained using a Cu Ka source, which contains peaks at 2θ angle values of 11.8, 15.3, 17.6, 19.0 and 23, 9 +/-0.2 degrees 2θ or 12.9, 18.5, 20.5, 21.9 and 26.3 +/-0.2 degrees 2θ.

The present invention includes tebipenem pivoxil malate crystalline salt Form A further characterized by the DSC profile essentially shown in FIG. eleven.

The present invention includes a crystalline salt Form A of tebipenem pivoxil malate further characterized by a DSC profile characterized by an endotherm with onset at 31.1°C and a minimum at 51.1°C and a second endotherm with onset at 117°C and a minimum at 127.6°C. WITH.

The present invention includes a crystalline salt form of tebipenem pivoxil methanesulfonate, wherein the XRPD of the Cu Ka source form contains characteristic data at the 2θ angle values shown in FIG. 12 (form B).

The present invention includes a crystalline salt form of tebipenem pivoxil methanesulfonate (Form B) wherein any 5, 6, 7, 8, 9, 10, 11, 12 or more of the following values on the XRPD of the Cu Ka source form: 9, 1, 9.6, 10.9, 12.6, 13.9, 14.6, 15.4, 17.2, 17.5, 18.2, 18.4, 18.7, 19.4, 19.6, 19.8, 20.4, 20.6, 21.5, 21.9, 22.2, 22.9, 23.6, 24.5, 25.3, 25.6, 26, 4, 26.9, 27.1, 27.5, 27.8, 28.0, 28.6, 29.4 or 29.8.

The present invention includes a crystalline salt form of tebipenem pivoxil methanesulfonate (form B) characterized by an XRPD pattern obtained using a Cu Ka source, which contains peaks at 2θ angle values of 9.6, 12.6, 15.4, 19.4 and 22, 2 +/-0.2 degrees 2θ or 10.9, 13.9, 17.2, 20.4 and 23.6 +/-0.2 degrees 2θ.

The present invention includes a crystalline salt Form B of tebipenem pivoxil methanesulfonate further characterized by the DSC profile essentially shown in FIG. 13.

The present invention includes a crystalline salt Form B of tebipenem pivoxil methanesulfonate further characterized by a DSC profile characterized by an endotherm with an onset at 57.8°C and a minimum at 88.5°C and a second endotherm with an onset at 175°C and a minimum at 177°C.

The present invention includes a crystalline salt form of tebipenem pivoxil hydrobromide, wherein the XRPD of the Cu Ka source form contains characteristic data at the 2θ angle values shown in FIG. 14 (form B).

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The present invention includes a crystalline salt form of tebipenem pivoxil hydrobromide (Form B) wherein, on the XRPD of the form prepared using a Cu Ka source, any 5,

6, 7, 8, 9, 10, 11, 12 or more of the following: 9.3, 9.5, 10.7, 12.6, 13.0, 14.0, 15.2, 15.7, 17.6, 18.7,

19.1, 20.0, 20.4, 20.8, 21.1, 21.9, 22.6, 23.5, 23.7, 24.9, 25.3, 25.5, 25, 8, 26.1, 26.5, 26.8, 27.3, 27.6, 28.4, 28.8,

29.4, 29.7, or 29.9 +/-0.2 degrees 2θ.

The present invention includes a crystalline salt form of tebipenem pivoxil hydrobromide (Form B) characterized by an XRPD pattern obtained using a Cu Ka source that contains peaks at 2θ angle values of 9.3, 13.0, 17.6, 20.8 and 26, 8 +/-0.2 degrees 2θ or 10.7, 14.0, 18.7, 20.0 and 23.5 +/-0.2 degrees 2θ.

The crystalline material comprises tebipenem pivoxil hydrobromide salt Form B further characterized by the DSC profile essentially shown in FIG. 15.

The present invention includes a crystalline salt form B of tebipenem pivoxil hydrobromide further characterized by a DSC profile characterized by an endotherm with onset at 32.9°C and a minimum at 66.3°C and a second endotherm with an onset at 186.8°C and a minimum at 190, 8°C.

The present invention includes a crystalline salt form of tebipenem pivoxil edisylate, wherein the form data obtained using a Cu Ka source contains the characteristic 2θ angle values shown in FIG. 16.

The present invention includes a crystalline salt form of tebipenem pivoxil edisylate (Form A) wherein any 5, 6, 7, 8, 9, 10, 11, 12 or more of the following values are present on the XRPD of the form prepared using a Cu Ka source: 4, 1, 5.0, 7.7, 8.2, 8.5, 9.5,10,1,13,1,13,5,15,4, 16, 16.9, 17.3, 18, 19.1, 20.3, 20.7, 21.2, 22.7, 23.1, 24.5, 25.7, 27.3, 28.8 +/-0.2 degrees 2θ.

The crystalline salt form of tebipenem pivoxil edisylate (form A) is characterized by an XRPD pattern obtained using a Cu Ka source, which contains peaks at 2θ angle values of 4.1, 8.2, 10.1, 20.3 and 21.2 +/- 0.2 degrees 2θ or 5.0, 10.1, 15.4, 18.0 and 20.7 +/- 0.2 degrees 2θ.

The present invention includes tebipenem pivoxil edisylate edisylate crystalline salt form A having a DSC profile essentially shown in FIG. 17.

The present invention includes a crystalline salt form (Form A) of tebipenem pivoxil edisylate further characterized by a DSC profile characterized by an endotherm with an onset at 56.3°C and a minimum at 79.3°C and a second endotherm with an onset at 144.5°C and a minimum at 157.5°C.

The present invention includes a crystalline salt form of tebipenem pivoxil according to any of FIGS. 1, 3, 5, 7, 9, 10, 12, 14, 16, 21 or 23, wherein the crystalline salt form of tebipenem pivoxil is at least 90%, 95%, 97%, 98%, 99% or 99.5% pure.

The present invention includes a pharmaceutical composition comprising a tebipenem pivoxil salt and a physiologically acceptable carrier, wherein the tebipenem pivoxil salt is at least 90%, 95%, 97%, 98%, 99%, or 99.5% of the crystalline tebipenem pivoxil salt of FIG. 1, 3, 5, 7, 9, 10, 12, 14, 16, 21 or 23. The pharmaceutical composition may be an intra-arterial, intravenous, injectable, topical, transmucosal, parenteral (including subcutaneous, intramuscular or bolus injection) dosage form , sublingual, transdermal, buccal or oral administration. The composition is an oral dosage form, for example in the form of a tablet or capsule.

In some embodiments, the pharmaceutical compositions and dosage forms provided herein include one or more crystal forms containing the tebipenem pivoxil salt.

Unit dosage forms of the present invention are suitable for oral, transmucosal (eg, nasal, sublingual, vaginal, buccal, or rectal), parenteral (eg, subcutaneous, intravenous, bolus, intramuscular, or intra-arterial) or transdermal administration to a patient. Examples of dosage forms include, without limitation, tablets; caplets; capsules such as soft elastic gelatin capsules; sachet; lozenges; lozenges; dispersion; suppositories; ointments; poultices (lotions); pastes; powders; bandages; cream; adhesive plasters; solutions; plasters; aerosols (eg, nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or transmucosal administration to a patient, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (eg, crystalline or amorphous solids) that can be dissolved to form liquid dosage forms suitable for parenteral administration to a patient.

The composition, form and type of dosage forms of the present invention, as a rule, will vary depending on their type of application. For example, a dosage form used in the acute treatment of a bacterial infection or associated disorder may contain higher amounts of one or more active ingredients than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain lower amounts of one or more active ingredients than an oral dosage form used in the treatment of the same disease or disorder. These and other variations, in which the dosage forms covered by the present invention will differ from each other, will be clearly apparent to experts in this field. See, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for inclusion in a pharmaceutical composition or dosage form depends on various factors well known in the art, including, without limitation, the route by which the dosage form will be administered to the patient. For example, oral dosage forms such as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the particular active ingredients in the dosage form.

The lactose-free compositions of the present invention may contain excipients which are well known in the art and are listed, for example, in the United States Pharmacopeia (USP) SP (XXI)/NF (XVI). Typically, lactose-free compositions contain the active ingredient, binder/filler and lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms contain the active ingredient, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

This invention also covers anhydrous pharmaceutical compositions and dosage forms containing active ingredients, since water can facilitate the decomposition of some compounds. For example, the addition of water (eg 5%) is widely used in the pharmaceutical field as a way to simulate extended storage to determine characteristics such as shelf life or stability of formulations over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of certain compounds. Thus, the effect of water on a formulation can be significant, as moisture and/or moisture is typically present during the manufacture, processing, packaging, storage, transport, and use of formulations.

The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared with anhydrous or low moisture ingredients and under low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that contain lactose and at least one active ingredient that contains a primary or secondary amine are preferably anhydrous if significant exposure to moisture and/or moisture is expected during manufacture, packaging and/or storage.

The anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Therefore, anhydrous compositions are preferably packaged with materials known to prevent exposure to water so that they can be included in suitable drug formulary kits. Examples of suitable packages include, without limitation, sealed foil packages, plastic packages, unit dose containers (eg, vials), blister packs, and blister packs.

This invention also covers pharmaceutical compositions and dosage forms that contain one or more compounds that reduce the rate at which the active ingredient will degrade. Such compounds, referred to herein as stabilizers, include, without limitation, antioxidants such as ascorbic acid, pH buffers, or saline buffers.

Similar to the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may vary depending on factors such as, but not limited to, the route by which it is administered to patients. However, typical dosage forms provided herein are provided in amounts ranging from about 1 mg to about 1000 mg per day, assuming a single dose per day in the morning, but preferably in divided doses throughout the day. More specifically, the daily dose is administered twice daily in divided doses. In particular, the daily dose range may be from about 5 mg to about 500 mg per day, more specifically from about 10 mg to about 200 mg per day. When treating a patient, therapy may begin at a lower dose, likely from about 1 mg to about 25 mg, and increase as necessary to a value from about 200 mg to about 1000 mg per day, either as a single dose or in divided doses, depending on the general reaction of the patient.

Dosage forms for oral administration. Pharmaceutical compositions by infusion

- 8 042386 of the present invention which are suitable for oral administration may be presented as discrete dosage forms such as, without limitation, tablets (eg chewable tablets), caplets, capsules and liquids (eg flavored syrups). Such dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmaceutical methods well known to those skilled in the art. See generally Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Conventional oral dosage forms of the present invention are prepared by combining the active ingredient(s) in a homogeneous mixture with at least one excipient according to conventional pharmaceutical formulation techniques. Excipients can take a wide variety of forms depending on the form of preparation required for administration. For example, excipients suitable for use in an oral liquid or aerosol dosage form include, without limitation, water, glycols, oils, alcohols, flavors, preservatives, and colorants. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules, and caplets) include, without limitation, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

Because of their ease of administration, tablets and capsules are the most preferred oral unit dosage forms in which solid excipients are used. If necessary, the tablets may be coated using standard aqueous or non-aqueous techniques. Such dosage forms can be obtained by any of the pharmaceutical methods. Typically, pharmaceutical compositions and dosage forms are prepared by uniformly and thoroughly mixing active ingredients with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired form.

For example, a tablet can be obtained by compression or molding. Compressed tablets can be obtained by compressing in a suitable machine the active ingredients in free-flowing form, such as powders or granules, optionally mixed with an excipient. Molded tablets can be obtained by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.

Examples of adjuvants that can be used in the oral dosage forms of the present invention include, without limitation, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose (eg, No. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Examples of excipients suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, without limitation, talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. The binder or excipient in the pharmaceutical compositions of the present invention is typically present in an amount of from about 50% to about 99% by weight of the pharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, without limitation, materials sold as AVICEL-PH-101™, AVICEL-PH-103™, AVICEL RC-581™, AVICEL-PH-105™ (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pennsylvania), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581™. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM™.

Disintegrants are used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may degrade on storage, while those containing too little may not degrade at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too large nor too small to adversely alter the release of the active ingredients should be used to prepare the oral solid dosage forms of the present invention. The amount of disintegrant used varies with the type of formulation and is readily apparent to one skilled in the art. Typical pharmaceutical compositions contain from about 0.5 to about wt.% disintegrant, in particular from about 1 to about 5 wt.% disintegrant.

Disintegrating agents that can be used in the pharmaceutical compositions and dosage forms of the present invention include, without limitation, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmelose sodium, crospovidone, potassium polacrilin, sodium starch glycolate, potato starch or tapioca starch, previously gelatinized starch, other starches, clays, other algins, other celluloses, gums and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosage forms of the present invention include, without limitation, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc , hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, siloid silica gel (AEROSIL 200™, manufactured by W.R. Grace Co., Baltimore, Maryland), coagulated synthetic silica aerosol (manufactured by Degussa Co., Plano, Texas), CAB-O-SIL™ (pyrogenic dioxide silicon sold by Cabot Co., Boston, Massachusetts) and mixtures thereof. When used, lubricants are typically used in an amount of less than about one weight percent of the pharmaceutical compositions or dosage forms in which they are incorporated.

Delayed Release Dosage Forms The tebipenem pivoxil salt crystalline forms provided herein can be administered by controlled release means or delivery devices that are well known to those skilled in the art. Examples include, without limitation, those described in US Pat. Nos. 3,845,770; 3916899; 3536809; 3598123 and 4008719, 5674533, 5059595, 5591767, 5120548, 5073543, 5639476, 5354556 and 5733566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydropropyl methylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide the desired profile. release in various proportions. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the present invention. The present invention thus encompasses unit dosage forms suitable for oral administration, such as, without limitation, tablets, capsules, gel capsules and caplets, which are adapted for controlled release.

All controlled release pharmaceutical products share the common goal of improving drug therapy relative to that achieved by their non-controlled release counterparts. Ideally, the use of an optimally designed controlled release formulation in medical treatment is characterized by using the minimum amount of drug substance to treat or control a condition for a minimum period of time. Advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency, and increased patient compliance with treatment regimens and regimens. In addition, controlled release formulations can be used to influence the time of onset of action or other characteristics, such as blood levels of the drug, and thus the occurrence of side (eg, adverse) effects can be influenced.

Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that quickly produces the desired therapeutic effect, and gradually and continuously release other amounts of drug to maintain that level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug that has been metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by various conditions, including, without limitation, pH, temperature, enzymes, water, or other physiological conditions or compounds.

Dosage forms for parenteral use. Parenteral dosage forms can be administered to patients by various routes, including, without limitation, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because they

- 10 042386 the introduction usually bypasses the natural defense mechanisms of patients from contaminants, dosage forms for parenteral use are preferably sterile or can be sterilized before administration to the patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

Suitable carrier media that can be used to provide the parenteral dosage forms of the present invention are well known to those skilled in the art. Examples include, without limitation, water for injection USP; aqueous carrier vehicles such as, but not limited to, saline for injection, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, and Ringer's lactic acid solution; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous carrier media such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients disclosed herein may also be included in parenteral dosage forms of the present invention.

Dosage forms for transdermal, topical and transmucosal use. Dosage forms for transdermal, topical and transmucosal use of the present invention include, without limitation, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to the person skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 and 1990) and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating oral mucosal tissue may be formulated as mouthwashes or oral gels. In addition, transdermal dosage forms include reservoir-type or matrix-type patches that can be applied to the skin and worn for a specific period of time to allow penetration of the desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide the transdermal, topical, and transmucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical art and depend on the particular tissue to which it will be applied. given pharmaceutical composition or dosage form. With this in mind, typical excipients include, without limitation, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof for the preparation of lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. Humectants or wetting agents can also be added to pharmaceutical compositions and dosage forms as needed. Examples of such additional ingredients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 and 1990).

Depending on the particular tissue being treated, additional components may be used before, with or after treatment with the active ingredients of the present invention. For example, penetration enhancers can be used to assist in the delivery of active ingredients to the tissue. Suitable penetration enhancers include, without limitation, acetone; various alcohols such as ethanol, oleyl and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; substances of the Kollidon class (povidone, polyvidone); urea; and various water-soluble or water-insoluble sugar esters such as Tween 80™ (polysorbate 80) and Span 60™ (sorbitan monostearate).

The pH of the pharmaceutical composition or dosage form, or the tissue to which the pharmaceutical composition or dosage form is applied, can also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of the solvent carrier, its ionic strength or tonicity can be adjusted to improve delivery. Compounds such as stearates may also be added to pharmaceutical compositions or dosage forms to preferably alter the hydrophilicity or lipophilicity of one or more active ingredients in order to improve delivery. In this case, stearates can serve as a lipid carrier medium for the composition, as an emulsifier or surfactant, and as a delivery or penetration enhancer. Various crystalline forms containing the active ingredients can be used to further control the properties of the resulting composition.

Sets. The present invention encompasses kits which, when used by a physician, can facilitate the administration of appropriate amounts of active ingredients to a patient.

A typical kit of the present invention contains a unit dosage form of the tebipenem pivoxil salt, or a pharmaceutically acceptable crystalline form or a prodrug thereof, and a unit dosage form of the second active ingredient. Examples of the second active ingredient include, without limitation, those listed herein.

The kits of the present invention may also contain devices that are used to administer the active ingredient(s). Examples of such devices include, without limitation, syringes, droppers, patches, and inhalers.

The kits of the present invention may also contain pharmaceutically acceptable carrier vehicles that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a crystalline form that needs to be reconstituted for parenteral administration, the kit may contain a sealed container with a suitable carrier medium in which the active ingredient can be dissolved to provide a sterile particle-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, without limitation, water for injection USP; aqueous carrier vehicles such as, but not limited to, saline for injection, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, and Ringer's lactic acid solution; water-miscible carrier media such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous carrier media such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The present invention includes a method of treating a bacterial infection comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising the crystalline tebipenem pivoxil salt of FIG. 1, 3, 5, 7, 9, 10, 12, 14, or 16. The method may include administering tebipenem pivoxil crystalline salt, wherein the composition contains an active agent in addition to tebipenem pivoxil crystalline salt. The method may include administering the crystalline salt of tebipenem pivoxil to the patient along with the active agent. The active agent may be an antibiotic. The bacterial infection may be an infection with Gram-negative bacteria, such as an infection with E. coli, an infection with Klebsiella pneumoniae, an infection with Acinetobacter baumannii, Pseudomonas aeruginosa, an infection with Neisseria gonorrhoeae, or an infection with Yersinia pestis.

Specific methods of the present invention may include the administration of an additional therapeutic agent, such as, without limitation, anti-inflammatory drugs, antihistamines, and decongestants. Examples of such additional therapeutic agents include, without limitation, antihistamines, including, without limitation, ethanolamines, ethylenediamines, piperazines, and phenothiazines; anti-inflammatory drugs; NSAIDS, including without limitation aspirin, salicylates, acetaminophen, indomethacin, sulindac, etodolac, fenamates, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, pyrazolone derivatives; and steroids, including without limitation corticosteroids and adrenocorticosteroids.

As noted above, certain crystal forms containing the tebipenem pivoxil salt can be used in the treatment or prevention of a wide range of bacterial infections. The amount of prophylactic or therapeutic dose of a particular active ingredient of the present invention in the acute or chronic treatment of a disease or condition may vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. The dose, and likely the frequency of dosing, will also vary according to the age, body weight, and response of the individual patient. Appropriate dosing regimens can be readily selected by those skilled in the art taking into account such factors. Generally, the recommended daily dosage range for the conditions described herein is in the range of about 1 mg to about 1000 mg per day, assuming a single dose per day, preferably in divided doses throughout the day. More specifically, the daily dose is administered twice daily in divided doses. In particular, the daily dose range may be from about 5 mg to about 500 mg per day, more specifically from about 10 mg to about 200 mg per day. In particular, the daily dose may be administered in 5, 10, 15, 20, 25, 50 or 100 mg dosage forms. When treating a patient, therapy will begin at a lower dose, likely from about 1 to about 25 mg, and increase as needed to about 200 to about 1000 mg per day, either as a single dose or in divided doses, depending from the general reaction of the patient. Alternatively, the daily dose is from 0.01 to 100 mg/kg.

In some cases, it may be necessary to use doses of the active ingredient outside the ranges disclosed herein, as will be apparent to those skilled in the art. In addition, it should be noted that the physician or attending physician will know how and when to interrupt, adjust, or terminate therapy in response to the individual patient's response.

As indicated above, the pharmaceutical composition of the present invention may also contain a pharmaceutically acceptable carrier, which may be any pharmaceutically acceptable excipient such as a binder, filler, lubricant, solvent, disintegrant or coating. Examples of a pharmaceutically acceptable carrier are provided above.

The crystalline salt of tebipenem pivoxil is usually present in a pharmaceutical composition in a therapeutically effective amount. As used herein, a therapeutically effective amount (or dose) is an amount that, when administered to a patient, results in a measurable improvement for the patient. It will be appreciated that the therapeutically effective amount will depend on the individual patient, the indication for which it is administered, and the effects of any co-administered drugs.

As also stated above, in an embodiment, the composition may be suitable for pharmaceutical use and may be in the form of a pharmaceutical composition. The pharmaceutical composition may take any suitable form and may be a tablet, capsule, solution, suspension, or a combination thereof.

The pharmaceutical composition can be used to treat a disorder, such as a bacterial infection. The therapeutic methods provided herein can be used to treat an existing disorder or to prevent, reduce the severity, or delay the onset of a disorder in a patient. Alternatively, or in addition, the compounds provided herein may be administered to a patient to prevent infection in a healthy patient. Patients include humans, domesticated animals (pets such as dogs) and farm animals. A method for treating a disorder may include administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical composition.

Pharmaceutical compositions may be packaged or used in the manufacture of a medicament for treatment. Packaged pharmaceutical preparations include containers containing a therapeutically effective amount of the crystalline tebipenem pivoxil salt and may also include labeling (eg, instructions) indicating how the contained composition is to be used to treat the disorder.

The present invention is further illustrated by the following examples, which should not be considered as limiting.

Examples

Instrumental methods.

The following instrumental procedures are used for the analysis of all crystalline forms, unless otherwise indicated.

X-ray powder diffraction (XRPD).

X-ray powder diffraction patterns were obtained on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA), a θ-2θ goniometer and V4 divergence and receiving slits, a Ge monochromator, and a Lynxeye detector. The performance of the instrument was verified using a certified corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and data was analyzed and presented using Diffrac Plus EVA v15.0.0.0. The samples were processed under ambient conditions in the form of flat plates, using the powder as received. The sample was neatly packed into a cavity cut into a polished zero background silicon wafer (510). The sample was rotated in its own plane during analysis. Acquisition details: angular range: 2-42° 2θ, step size: 0.05° 2θ, and acquisition time: 0.5 s/step. Differential Scanning Calorimetry (DSC) DSC was performed using a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a cooling system with a 40 ml/min N2 purge. DSC thermograms were obtained at 5° C./min in crimped Al containers.

DSC data was also obtained on a TA Instruments Q2000 equipped with a 50 position autosampler. Calibration for heat capacity was performed with sapphire, and calibration for energy and temperature was performed with certified indium. Typically, 0.5-3 mg of each sample in a pinched aluminum container was heated at 10°C/min from 25 to 300°C. Dry nitrogen purge was maintained at 50 ml/min over the sample.

Thermogravimetric analysis (TGA).

TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer equipped with a 16-position autosampler by purging 40 ml/min N2 at 5°C/min in Pt or Al containers. The instrument was temperature calibrated using certified alumel and nickel. Typically, 5-10 mg of each sample was loaded into a predetermined weight aluminum DSC container and heated at 10°C/min from ambient temperature to 300°C. Nitrogen purge was maintained at 60 ml/min over the sample.

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High pressure liquid chromatography (HPLC).

Purity analysis was performed on an Agilent HP1100 Series system equipped with a diode array detector and using ChemStation vB.04.03 software using Method A or Method B as detailed below.

Table A. HPLC Method A for Chemical Purity Parameter Meaning Way Type Reverse phase with gradient elution Getting a Sample 0.5 mg/ml in acetonitrile Column Supelco Ascentis Express C18, 100 x 4.6 mm, 2.7 microns Column temperature (°C) 25 Injection (1) 3 or 5 Wavelength, bandwidth (nm) 255, 90 Flow rate (ml/min.) 2 Phase A 0.1% TFA in water Phase B 0.085% TFA in acetonitrile Schedule Time (min.) % phase A % phase B 0 95 5 6 5 95 6.2 95 5 8 95 5

HPLC analysis was performed according to method B on an Agilent HP1100/1200 system equipped with a diode array detector and using Chemstation software. The analysis was performed using an Agilent LiChrospher 100 RP-18, 5 µm, 250x4 mm reverse phase column under isocratic conditions at ambient temperature. Prior to injection, the sample concentration was approximately 0.5 mg/ml in acetonitrile-water 1:1 (v/v) and the injection volume was 10 μl. The mobile phase was 68/30/2 (v/v/v) 50 mM ammonium acetate in water/acetonitrile/triethylamine, pH adjusted to 3.5 with concentrated phosphoric acid. The flow rate was 0.8 ml/min and the running time was 15 minutes. Detection occurred at a wavelength of 330 nm.

Proton nuclear magnetic resonance ( ¹ H-NMR).

NMR spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and adjusted using a DRX400 control panel. Automated experiments were performed with ICONNMR v4.0.7 running Topspin v1.3 using standard Bruker loaded experiments. Samples were obtained at a concentration of 2-5 mg/ml by dissolving in DMSO-d ₆ solvent. Offline analysis was performed using ACD Spectrus Processor 2014.

Comparative Example 1 Crystal form of tebipenem pivoxil.

Tebipenem pivoxil crystalline Form A was prepared according to known methods. An XRPD diffraction pattern of crystalline tebipenem pivoxil was obtained (FIG. 18). The XRPD diffraction pattern of crystalline tebipenem pivoxil showed the peaks shown in Table 1. 1.

- 14 042386

Table 1. Characteristic angles of form A of tebipenem pivoxil (2Θ) Characteristic angle (°) Relative intensity(%) 9.55 29.12 11.00 25.06 12.80 23.14 13.25 21.78 15.40 20.77 17.95 100.00 19.20 20.32 20.35 51.69 21.10 64.79

Table 1. Characteristic angles of form A of tebipenem pivoxil(20) Characteristic angle (°) Relative intensity (%) 23.85 33.18 25.80 21.78 26.40 20.65 27.75 23.36 28.75 24.27 37.50 25.62

DSC data (not shown) of crystalline tebipenem pivoxil showed a sharp endotherm at 132.1°C followed by two separate exotherms at 161.8 and 175.9°C. The TGA results showed a gradual decrease that started at approximately 109.5°C and a rapid decrease after 169.2°C. Crystalline tebipenem pivoxil exhibited approximately 2% weight loss at 109.5 to 169.2°C.

^-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.07-1.16 (m, 15 H) 1.19 (s, 1H) 1.98-1.99 (m, 1H) 2 .73 (s, 1H) 2.89 (s, 1H) 3.07 (s, 1H) 3.24 (dd, J=6.25, 2.59 Hz, 1H) 3.27-3.27 ( m, 1H) 3.31-3.38 (m, 3H) 3.73 (td, J=6.79, 3.60 Hz, 2H) 3.87 (t, J=7.58 Hz, 2H) 3.91-4.01 (m, 1H) 4.03 (d, J=7.07 Hz, 1H) 4.18 (dd, J=9.35, 2.65 Hz, 1H) 4.27- 4.39 (m, 3H) 5.09 (d, J=5.18 Hz, 1H) 5.74 (d, J=5.94 Hz, 1H) 5.89 (d, J=5.94 Hz , 1H) 7.95 (s, 1H).

Comparative Example 2 Tebipenem Pivoxil Hydrochloride (HCL) Crystalline Salt Form A.

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μl). Then the acidic stock solution (1 M HCl in THF) was added to 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 0°C for 2 hours (0.2°C/min) and kept at 0°C for approximately 2 hours. The resulting slurry was filtered with a fritted filter and air dried on a filter block at ambient conditions for 15 minutes. This sample was found to be 99.5% pure by HPLC (Method A). The XRPD pattern for this crystal form is shown in FIG. 19, and the list of peaks is presented in table. 2.

A crystalline tebipenem pivoxil HCl salt of the same form was also prepared in equivalent purity by the method of the previous paragraph with the following modifications. Tebipenem pivoxil was dissolved in EtOH (930 µl). Then the acidic stock solution (1 M HCl in THF) was added to 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 5°C for 2 hours (0.2°C/min) and kept at 5°C for approximately 2 hours.

- 15 042386

Table 2. Characteristic angles (2Θ) of the salt form A of tebipenem pivoxil hydrochloride Characteristic angle (°) Relative intensity(%) 6.2 4.6 7.2 2.8 9.4 17.5 10.9 14.1 12.5 3.5 12.6 7.1 13 7.8 14.1 3.7 15.4 9.9 15.8 2.3 17.9 100 18.1 4.1 19.1 4.8 20.2 29.4 20.9 29.1 21.1 9.2 21.9 1.9 22.1 3.4 22.8 6.1 23.7 12.8

Table 2. Characteristic angles (2Θ) of the salt form A of tebipenem pivoxil hydrochloride Characteristic angle (°) Relative intensity(%) 23.8 10.5 25.2 5.6 25.5 7.1 25.7 4.7 26.1 3.9 26.3 8.5 26.8 h, h 27.1 7.5 27.7 8.4 28.3 3.6 28.6 8.1 29.1 2.7 29.4 h, h thirty 5

DSC profile for the crystalline salt form A of tebipenem pivoxil hydrochloride (Fig.

20) showed a broad endotherm with an onset at 29.4°C and a minimum at 56°C and a melting enthalpy of 38 J/g. The DSC results also showed an exotherm with decomposition onset at

194.8°C.

The TGA results (also shown in FIG. 17) showed a 2.2% weight loss at

- 16 042386 from room temperature to 100°C. No other thermal events were recorded prior to the start of decomposition at approximately 150°C.

¹ H-NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.18 (m, 15H) 2.08 (s, 1H) 3.28 (dd, J=6.19, 2, 65 Hz, 1H) 3.30-3.41 (m, 2H) 3.42-3.42 (m, 1H) 3.61-3.68 (m, 2H) 3.89-4.01 (m , 3H) 4.14-4.27 (m, 3H) 4.404.50 (m, 1H) 4.69-4.81 (m, 2H) 5.14 (br s, 1H) 5.75 (d, J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10.46 (s, 1H). ¹ H-NMR and HPLC were repeated after 1 week of storage at 40°C/75% relative humidity. Tebipenem pivoxil hydrochloride crystalline form A was obtained and determined to be 98.9% pure by HPLC.

Example 1 Crystalline salt of tebipenem pivoxil ethanesulfonate (ESA).

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μl), then an acidic stock solution (1 M ethanesulfonate acid in THF) was added in 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device (Cambridge Reactor Design) for 20 minutes. Then the sample was cooled to 0°C for 2 hours (0.2°C/min) and kept at 0°C for ~2 hours. Precipitation was not observed. The sample was then cooled at 0.5°C/min to -15°C at 0.5°C/min and stored at -20°C for 2 days. The solution was transferred to a 20 ml scintillation vial and the antisolvent (tert-methylbutyl ether, TBME) was added slowly with stirring at 25°C, 500 rpm until a precipitate formed in a ratio of 10:1 antisolvent:solvent (v/v ). The resulting slurry was filtered with a fritted filter and air dried on a filter block at ambient conditions for 15 minutes.

The XRPD spectra for crystal form A of tebipenem pivoxil ethanesulfonate are shown in FIG. 1. The XRPD diffraction pattern for this crystalline form showed the characteristic peaks shown in Table 1. 3. A sample of tebipenem pivoxil ethanesulfonate ethanesulfonate salt form A (esilate) was determined to be 98.9% pure by HPLC method A.

XRPD and HPLC analyzes were performed again after one week of storage at 40° C., 75% relative humidity. The XRPD spectra were essentially unchanged, however, the sample was found to have a substantially low purity of 80.7% HPLC method A.

Table 3. Characteristic angles (2Θ) of the salt form A of tebipenem pivoxil ethanesulfonate Characteristic angle (°) Relative intensity (%) 5.7 23.7 8.8 12.8 9.6 29.5 10.8 45.5 12.4 29.8

- 17 042386

Table 3 Characteristics of tebipenem pi ethanesulfonate Characteristic angle (°) 13.7 15.1 16.9 17.8 18.4 18.7 19.0 19.3 20.0 20.3 21.0 21.8 22.1 22.4 23.0 23.4 24.9 25.2 25.9 26.2 26.5 26.8 27.2 27.9 28.6 29.2 29.7

e angles (2Θ) of the salt form A [voxila Relative intensity(%) 32.5 84.4 87.1 23 29.8 41.6 100 46.1 22 55.5 40 23.6 89.5 14.9 29.4 16.4 11.8 16.4 thirty 17.1 19.1 19.1 17 48.7 15.8 16.3 16.5

The DSC profile for the crystalline salt form A of tebipenem pivoxil ethanesulfonate (FIG. 2) showed a broad endotherm starting at 70.8°C with two minima, the first at 90.7°C and the second at approximately 108°C, with a fusion enthalpy of 116 J /g for the first minimum and 19 J/g for the second. Decomposition occurs at temperatures above 150°C for this form.

The TGA results (also shown in FIG. 2) showed gradual degradation from room temperature to 110° C. with a 2.9% weight loss. No other thermal events were recorded prior to the onset of decomposition starting at approximately 150°C.

¹ H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (t, J=7.45 Hz, 3H) 1.07-1.16 (m, 15H) 2.35 (q, J =7.37 Hz, 2H) 3.07 (s, 1H) 3.28 (dd, J=6.13, 2.72 Hz, 1H) 3.34 (s, 17H) 3.60-3.68 (m, 2H) 3.93 (br t, J=7.52 Hz, 3H) 4.12-4.17 (m, 1H) 4.19 (br d, J=9.47 Hz, 2H) 4 .21-4.24 (m, 1H) 4.40-4.49 (m, 1H) 4.68-4.77 (m, 2H) 5.11 (br d, J=4.80 Hz, 1H ) 5.75 (d, J=5.81 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10.11 (br s, 1H). 1HNMR results were consistent with pure tebipenem pivoxil. Observed 1.0 eq. esylate counterion.

Example 2 Crystalline Salt Form A of Tebipenem Pivoxil Ketoglutarate (KTG)

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μl). Then an acidic stock solution (1M malic acid in THF) was added in 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 5°C for 2 hours (0.25°C/min) and kept at 5°C for ~2 hours. Precipitation was not observed, so the sample was cooled to -15°C at 0.5°C/min and stored at -20°C for 2 days. The solution was transferred to a 20 ml scintillation vial and anti-solvent (tert-18 042386 methyl butyl ether, TBME) was added slowly with stirring at 20°C, 500 rpm in a ratio of 10:1 anti-solvent:solvent (v/v). After stirring for 24 hours a precipitate formed which was filtered off with a fritted filter and air dried on the filter block at ambient conditions for 15 minutes.

The XRPD spectra for the crystalline salt form A of tebipenem pivoxil ketoglutarate are shown in FIG. 3. On the XRPD diffraction pattern for this crystalline form, characteristic peaks appeared, indicated in table. 4. A sample of tebipenem pivoxil ketoglutarate salt crystalline form A was determined to be 94.5% pure by HPLC method A.

An attempt was made to repeat the XRPD and HPLC assays after one week of storage at 40° C., 75% relative humidity. After storage, XRPD spectra could not be obtained because the sample became liquid.

- 19 042386

Table 4. Characteristic angles (2Θ) of the salt form A of tebipenem pivoxil ketoglutarate Characteristic angle (°) Relative intensity (%) 26.7 35.4 27.1 26.3 27.4 22.6 28.3 17.8 28.7 25.2 29.6 18

The DSC profile for the crystalline salt form A of tebipenem pivoxil ketoglutarate (Fig. 4) showed a wide endotherm starting at 36.6°C and minimizing at 57.0°C with a melting enthalpy of 10 J/g, a second endotherm starting at 106, 5°C and a minimum at 117.0°C with a heat of fusion of 12 J/g and an exotherm peaking at 126.4°C upon decomposition.

The TGA results (also shown in FIG. 4) showed a 0.7% weight loss from room temperature to 75°C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.06-1.17 (m, 16H) 2.45 (t, J=6.63 Hz, 2H) 2.85 (br t , J=6.25 Hz, 2H) 2.97-2.97 (m, 1H) 3.24-3.27 (m, 2H) 3.28-3.40 (m, 21H) 3.43 ( s, 4H) 3.81-3.92 (m, 4H) 3.934.00 (m, 1H) 4.18 (dd, J=9.47, 2.65 Hz, 1H) 4.31-4.38 (m, 1H) 4.44 (d, J=8.46 Hz, 2H) 4.98-4.98 (m, 1H) 5.10 (br s, 1H) 5.74 (d, J=5 .81 Hz, 1H) 5.89 (d, J=5.94 Hz, 1H). ¹ H-NMR results were consistent with pure tebipenem pivoxil. Observed 1.0 eq. ketoglutarate counterion.

Example 3 Crystalline Maleate Salt Form A (MAE) of tebipenem pivoxil.

Tebipenem pivoxil (J07492, 35 mg) was dissolved in MeCN (270 μl), then an acidic stock solution (1M maleic acid in THF) was added in 1 mol equiv. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 0°C for 2 hours (0.2°C/min) and kept at 0°C for approximately 1-2 hours. The solution was transferred to a 20 ml scintillation vial and the anti-solvent (tert-methylbutyl ester, TBME) was slowly added with stirring at 20° C., 500 rpm in a ratio of 4:1 anti-solvent: solvent (v/v). After stirring for 24 hours a precipitate formed which was filtered off with a fritted filter and air dried on the filter block at ambient conditions for 15 minutes.

The XRPD spectra for the crystalline salt Form A of tebipenem pivoxil maleate are shown in FIG. 5. The XRPD diffraction pattern for this crystalline form exhibited the characteristic peaks shown in Table 1. 5. A sample of crystal form A of the tebipenem maleate salt of pivoxil was determined to be 99.3% pure by HPLC method A.

XRPD and HPLC analyzes were repeated after one week of storage at 40°C, 75% relative humidity. XRPD showed that form A had converted to form B. Salt form B of tebipenem pivoxil maleate after storage had a purity of 78.6% according to HPLC, method A.

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Table 5. Characteristic angles (2Θ) of the salt form A of tebipenem pivoxil maleate Characteristic angle (°) Relative intensity (%) 8.0 36.9 8.6 22.7 10.8 13.0 AND 2 16.7 I,9 16.4 12.2 20.1 12.6 58.2 15.0 43.6 15.4 44.6 15.7 42.0 16.9 36.5 18.2 37.4 18.7 100 19.4 43.9 19.9 66.0 20.4 44.0 21.2 33.9 Table 5. Characteristic angles (2Θ) of the salt form A of tebipenem pivoxil maleate Characteristic angle (°) Relative intensity(%) 22.5 24.4 23.1 20.6 24.2 24.4 24.8 51.0 25.7 37.8 26.5 41.4 27.5 17.8 28.3 21.0

The DSC profile for tebipenem pivoxil maleate crystalline salt form A (Fig. 6) showed a broad melting endotherm starting at 50.6°C with a minimum at 74.3°C with a melting enthalpy of 53 J/g, a second endotherm starting at 103, 0°C and a minimum at 110.1°C with a melting enthalpy of 32 J/g and an exotherm peaking at 139.5°C before decomposition.

The TGA results (also shown in FIG. 6) showed a 3.6% weight loss from room temperature to 100°C.

1H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.06-1.18 (m, 16H) 2.07 (s, 1H) 3.07 (s, 1H) 3.073.08 (m, 1H) 3.12-3.12 (m, 1H) 3.27 (dd, J=6.19, 2.78 Hz, 2H) 3.34 (br dd, J=9.28, 7.26 Hz , 5H) 3.60 (t, J=7.52 Hz, 2H) 3.89-4.01 (m, 3H) 4.07-4.22 (m, 3H) 4.38-4.47 ( m, 1H) 4.67 (td, J=8.87, 3.85 Hz, 2H) 5.11 (br d, J=5.05 Hz, 1H) 5.75 (d, J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 6.05 (s, 2H). ¹ H-NMR results were consistent with pure tebipenem pivoxil. Observed 0.97 eq. maleate counterion.

Example 4 Crystalline Salt Form B Maleate (MAE) of Tebipenem Pivoxil.

The crystalline salt form B of tebipenem pivoxil maleate was prepared as follows. Tebipenem pivoxil (mg) was dissolved in MeCN (270 μl). Then an acidic stock solution (1M maleic acid in THF) was added in 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 5°C for 2 hours (0.25°C/min) and kept at 5°C for approximately 2 hours.

Precipitation was not observed. The sample was then cooled to -15°C at 0.5°C/min and stored at -20°C for

- 21 042386 within 2 days. The solution was transferred to a 20 ml scintillation vial and anti-solvent (tert-methylbutyl ether, TBME) was slowly added with stirring at 25° C., 500 rpm in a ratio of 5:1 anti-solvent:solvent (v/v). A precipitate formed after stirring for 24 hours. The precipitate was filtered off with a fritted filter and air dried on a filter block at ambient conditions for 15 minutes.

The XRPD diffraction pattern for this crystalline form exhibited the characteristic peaks shown in Table 1. 6.

The XRPD spectra for the crystalline salt form B of tebipenem pivoxil maleate are shown in FIG. 7. Sample Crystal Form B of the tebipenem maleate salt of pivoxil was determined to be 99.3% pure by HPLC method A.

XRPD and HPLC analyzes were repeated after one week of storage at 40°C, 75% relative humidity. XRPD showed characteristic peaks for tebipenem pivoxil maleate crystalline Form B. Salt form B of tebipenem pivoxil maleate after storage was 90.2% pure according to HPLC method A.

Table 6. Characteristic angles (2Θ) of the salt form B of tebipenem pivoxil maleate Characteristic angle (°) Relative intensity(%) 5.5 24 8.9 29.1 Yu,1 14.7 10.6 Yu,1 and about 34.5 12.8 15.7 13.6 25.5 14.3 19.8 14.9 6.8 16.7 28.4 17.0 88.2

- 22 042386

Table 6. Characteristic angles (2Θ) of the salt form B of tebipenem pivoxil maleate Characteristic angle (°) Relative intensity(%) 17.2 29.6 17.9 7.4 18.6 41.8 19.0 29.1 19.4 14.5 20.2 32.7 20.5 16.2 20.8 53.9 21.4 100 21.9 25.8 22.2 26.3 23.1 14.5 24.0 43 24.5 from 25.1 11.8 25.5 16.3 26.2 16.2 27.5 17.8 28.1 19.1 28.9 16.8 29.6 10.6

The DSC profile for the crystalline salt form B of tebipenem pivoxil maleate (Fig. 8) showed a wide endotherm starting at 40.3°C with a minimum at 65.3°C and a fusion enthalpy of 77 J/g, a second endotherm starting at 114.7 °C and a minimum at 119.6 °C with a melting enthalpy of 25 J/g and an exotherm peaking at 140.3 °C before decomposition.

The TGA results (also shown in FIG. 8) showed a 4.6% weight loss from room temperature to 100°C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm -0.21 - -0.21 (m, 1H) 1.07-1.16 (m, 15H) 3.07 (s, 1H ) 3.27 (dd, J=6.19, 2.78 Hz, 2H) 3.29-3.40 (m, 23H) 3.60 (t, J=7.52 Hz, 2H) 3, 89-4.02 (m, 3H) 4.06-4.16 (m, 2H) 4.19 (dd, J=9.54, 2.72 Hz, 1H) 4.37-4.48 (m , 1H) 4.61-4.73 (m, 2H) 5.11 (d, J=5.18 Hz, 1H) 5.75 (d, J=5.81 Hz, 1H) 5.89 (d , J=5.94 Hz, 1H) 6.05 (s, 2H). ¹ H-NMR results were consistent with pure tebipenem pivoxil. Approximately 0.92 eq. maleate counterion.

Example 5 Crystalline Salt Form A of Tebipenem Pivoxil Malate (MAL)

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μl). An acidic stock solution (1M malic acid in THF) was added in 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 0°C for 2 hours (0.2°C/min) and kept at 0°C for approximately 2 hours. Precipitation was not observed, so the sample was cooled to -15°C at 0.5°C/min and stored at -20°C for 2 days. The solution was transferred to a 20 ml scintillation vial and anti-solvent (tert-methylbutyl ether, TBME) was slowly added with stirring at 25° C., 500 rpm in a 4:1 anti-solvent/solvent (v/v) ratio. After stirring for 24 hours a precipitate formed which was filtered off with a fritted filter and air dried on the filter block at ambient conditions for 15 minutes. An XRPD diffraction pattern for crystals obtained according to this procedure is shown in FIG. 9. The list of peaks for this diffraction pattern is presented in Table. 7.

Tebipenem pivoxil malate crystalline salt was also prepared in equivalent purity by the method of the previous paragraph, but with the following modifications. Tebipenem pivoxil was dissolved in EtOH (930 µl). An acidic stock solution (1M malic acid in THF) was added to 1

- 23 042386 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 5°C for 2 hours (0.2°C/min) and kept at 5°C for approximately 2 hours. The sample was then cooled to -15°C at 0.2°C/min and stored at 20°C for 24 hours. The solution was transferred to a 20 ml scintillation vial and anti-solvent (n-hexane) was added slowly with stirring at 25° C., 500 rpm until a precipitate formed in a 3:1 anti-solvent:solvent (v/v) ratio. The resulting slurry was filtered with a fritted filter and air dried on a filter block at ambient conditions for 15 minutes. The XRPD data for crystals obtained by this method are shown in FIG. 10.

Table 7. Characteristic angles (2Θ) of the salt form A of tebipenem pivoxil malate Characteristic angle (°) Relative intensity (%) 9.1 22.9 9.3 18.7 and about I,4 11.8 25.4 12.3 12.9 12.9 23.6 13.1 21.4 14.4 I,9 14.9 14.2 15.3 35.1 16.0 20.1 16.6 15.9 17.6 89.3 18.5 56.5 19.0 100 19.9 26.6 20.5 81.6 20.8 28.6 21.4 20.6 21.9 37.1 22.2 33.1 23.1 14.9 23.4 16.2 23.9 36.8 24.8 20.4 25.5 17.2 26.0 20.1 26.3 27.1 Table 7. Characteristic angles (2Θ) of the salt form A of tebipenem pivoxil malate Characteristic angle (°) Relative intensity(%) 27.7 25.9 28.4 24.4

The DSC profile for the crystalline salt Form A of tebipenem pivoxil malate (Fig. 11) showed a melting endotherm starting at 32.1°C with a minimum at 51.1°C and a melting enthalpy of 9 J/g, with a second endotherm with onset at 117.0°C and a minimum at 127.6°C with a heat of fusion of 23 J/g and an exotherm peaking at 131.6°C with a heat of 44 J/g.

The TGA results (also shown in FIG. 11) showed 0.7% weight loss from room temperature to 75°C and 0.3% weight loss from 75°C to 130°C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.07-1.16 (m, 16H) 2.41 (dd, J=15.66, 7.20 Hz, 1H) 2, 59 (dd, J=15.60, 5.75 Hz, 1H) 3.07 (s, 1H) 3.25 (dd, J=6.32, 2.65 Hz, 1H) 3.32 (br dd , J=9.35, 7.33 Hz, 5H) 3.39 (t, J=7.52 Hz, 3H) 3.68-3.68 (m, 1H) 3.76-3.83 (m , 2H) 3.88 (t, J=7.58 Hz, 2H) 3.96 (br s, 1H) 4.15-4.18 (m, 1H) 4.15-4.22 (m, 1H ) 4.29-4.44 (m, 3H) 5.04-5.04 (m, 1H) 5.09 (br s, 1H) 5.74 (d, J=5.94 Hz, 1H) 5 .89 (d, J=5.94 Hz, 1H). ¹ H-NMR results were consistent with pure tebipenem pivoxil. Approximately 1.09 eq. malate counterion. XRPD was tried after one week of storage at 40°C and 75% relative humidity. The sample was found to have liquefied as an orange liquid. HPLC analysis after sample storage was not performed.

Example 6 Salt form B of tebipenem pivoxil methanesulfonate (MSA).

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μl). Then the acidic stock solution (1M methanesulfonic acid in THF) was added in 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 0°C for 2 hours (0.2°C/min) and kept at 0°C for approximately 2 hours. Precipitation was not observed, so the sample was cooled to -15°C at 0.5°C/min and stored at -20°C for 2 days. The solution was transferred to a 20 ml scintillation vial and the anti-solvent (tert-methylbutyl ether, TBME) was slowly added with stirring at 25°C, 500 rpm until a precipitate formed in a ratio of 3:1 anti-solvent: solvent (v/v ). The resulting slurry was filtered with a fritted filter and air dried on a filter block at ambient conditions for 15 minutes. The crystalline material obtained by this procedure was determined to be 99.5% pure according to HPLC method A. The XRPD pattern for this form is shown in FIG. 12. Characteristic peaks are presented in table. 8.

Salt MSA was also obtained in the same crystalline form with equivalent purity using the method of the previous paragraph, but with the following changes. Tebipenem pivoxil was dissolved in EtOH (930 µl). An acidic stock solution (1 M methanesulfonic acid in THF) was added in 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 5°C for 2 hours (0.2°C/min) and kept at 5°C for approximately 2 hours. The sample was then cooled to -15°C at 0.2°C/min and stored at 20°C for 24 hours. The solution was transferred to a 20 ml scintillation vial and anti-solvent (n-hexane) was added slowly with stirring at 25° C., 500 rpm until a precipitate formed in a 3:1 anti-solvent:solvent (v/v) ratio. The resulting slurry was filtered with a fritted filter and air dried on a filter block at ambient conditions for 15 minutes.

Table 8. Characteristic angles (2Θ) of salt form B of tebipenem pivoxil methanesulfonate Characteristic angle (°) Relative intensity (%) 9.1 10.8 9.6 31.5 10.9 33.8 12.6 24.6 13.9 27 14.6 6.2 15.4 54.5 17.2 90.1 17.5 12.4 18.2 17.2

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Table 8. Characteristic angles (2Θ) of salt form B of tebipenem pivoxil methanesulfonate Characteristic angle (°) Relative intensity (%) 18.4 41.7 18.7 30.7 19.4 100 19.6 66.5 19.8 33.1 20.4 67.1 20.6 20.5 21.5 46.9 21.9 17.1 22.2 99.8 22.9 18 23.6 23.4 24.5 12.2 25.3 I,1 25.6 13.8 26.4 16.3 26.9 22.3 27.1 15.8 27.5 9 27.8 13.1 28.0 24.1 28.6 32.1 29.4 25.8 29.8 13.8

The DSC profile for crystalline salt form B of tebipenem pivoxil methanesulfonate (Fig. 13) showed a melting endotherm starting at 57.8°C with a minimum at 88.5°C and a heat of fusion of 105 J/g, a second endotherm starting at 175.2 °C and a minimum at 177.0°C with a heat of fusion of 48 J/g before decomposition.

The TGA results (also shown in FIG. 13) showed a 2.9% weight loss from room temperature to 100°C. No other thermal events were noted prior to decomposition.

1H-NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.18 (m, 16H) 2.07 (s, 1H) 2.30 (s, 2H) 2.272.31 (m, 1H ) 3.07 (s, 1H) 3.28 (dd, J=6.13, 2.59 Hz, 1H) 3.30-3.46 (m, 6H) 3.61-3.69 (m, 2H) 3.90-4.01 (m, 3H) 4.13-4.28 (m, 3H) 4.40-4.50 (m, 1H) 4.70-4.79 (m, 2H) 5.11 (br s, 1H) 5.75 (d, J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10.12 (br s, 1H). ¹ H-NMR results (not shown) were consistent with pure tebipenem pivoxil. Approximately 1.06 eq. methanesulfonate counterion if the assay was corrected for solvent by TGA. XRPD and HPLC were performed after one week of storage at 40°C and 75% relative humidity. The XRPD pattern was consistent with pure crystalline form B of tebipenem pivoxil methanesulfonate. The sample was 99.0% pure by HPLC method A.

Example 7 Preparative synthesis of tebipenem pivoxil HBR methanesulfonate (MSA) salt form B.

Tebipenem pivoxil (125 mg) was placed in eight separate 20 ml scintillation vials and dissolved in MeCN (7.5 vol., 940 μl) with stirring at 25°C, 500 rpm using a magnetic stirrer on a Polar Bear device. The sample was treated with 1 mol-eq. acidic stock solution (1M stock solution of methanesulfonic acid in THF) and cooled to 5°C. At 5°C, precipitation was not observed and the temperature was raised to 20°C. Antisolvent (TBME) was then added with stirring at 20° C. in a ratio of 2:1 (antisolvent:solvent (v/v)) over 1 hour. The resulting suspensions were filtered through a fritted filter, dried under vacuum for 15 minutes, and each sample was analyzed by XRPD. Samples that exhibited the Form B mesylate XRPD structure were pooled together for characterization. The characteristic peaks of the XRPD diffraction pattern are presented in Table 1. 10.

Table 9 Solid phase characterization of Form B MSA of tebipenem pivoxil on an enlarged scale Received with Addition of antisolvent at 20°C (TBME:MeCN, 2:1) XRPD Crystal form B mesylate Ή-NMR Ή-NMR results match the structure. -1.03 eq. mesylate, -0.03 eq. ACN Anion IC (equiv.) 0.97 (not corrected for solvent) HPLC Method B 99.4% GVS Analysis (gravimetric vapor sorption) and XRPD after GVS The sample is hygroscopic. 6.2% absorption from 0 to 90% RH. Isotherm shows a step change from 0 to 10% RH (3.0 wt%) and from 80 to 90% RH (1.4 wt%) No change in XRPD after GVS. DSC Wide endotherm at 68.8°C (beginning), 88 J/g. Endotherm at 140.7°C (beginning), 16 J/g, ~160°C before decomposition. TGA 3.5 wt. % loss at temperatures from RT to 120°C. KF 3.3% water, - 1 eq. water PLM Crystals and particles, diameter 10-150 µm XRPD analysis after storage at 40°C/75% RH and 25°C/97% RH for 1-4 weeks Invariably according to XRPD after 1 week, and thus represented powder after 25/97 but after 40/75 was resin. HPLC at 1 week: 40/75: 95.5%, 25/97: 96.5%. The sample turned into a liquid

Table 9 Solid phase characterization of Form B MSA of tebipenem pivoxil on an enlarged scale condition within 2 weeks VT-XRPD on C2 Some changes when heated to 100°C. Sample decomposed ~160°С

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Example 8 Tebipenem pivoxil methanesulfonate (MSA) salt form.

Tebipenem pivoxil (1 g) was dissolved in MeCN (8 vol., 8 ml) and 1 mol equiv was added. acidic stock solution (1 M methanesulfonic acid in THF, 2 ml) with stirring at 25°C, 500 rpm. and a precipitate began to form. Additional anti-solvent was added to a ratio of 5:1 and then the precipitate was cooled to 0° C. at 0.2° C./min. When 0° C. was reached, the sample was removed and rapidly cooled in a dry ice/acetone bath to complete the precipitation. The solid was filtered off under vacuum through a Buchner funnel and dried under vacuum at rt. within 16 hours.

XRPD analysis of the resulting solid showed that the material was a mixture of Form C and Form B mesylate. A pure form C sample could not be obtained, therefore this sample was further characterized as detailed below. The XRPD pattern for Form C + Form B is shown in FIG. 25 and the DSC and TGA plots are shown in FIG. 26.

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Table 11 Solid Phase Characterization Form C + Form B Tebipenem Pivoxil Mesylate Received from help Addition of antisolvent at 25°C (TBME:MeCN, 2:1) XRPD Crystal form C + form B mesylate Ή-NMR The results of Ή-NMR are consistent with the structure. ~1.08 equiv. mesylate. Traces of residual MeCN and TBME are visible. Anion IC (equiv.) 1.01 (not corrected for solvent) HPLC Method B 99.1% Analysis of GVS and XRPD after GVS The sample is hygroscopic. 10.0% absorption from 0 to 90% RH with two steps at 0-10% and 80-90% RH. Reversible absorption and loss. XRPD after GVS showed a precursor to Form B mesylate. DSC Wide endotherm from 30 to 120°C. Peak at 88.2°C, 75 J/g. The sample decomposes at ~140°C. TGA 3.5 wt. % loss at temperatures from RT to 120°C. KF Didn't carry out PLM Didn't carry out XRPD analysis after storage at 40°C/75% RH and 25°C/97% RH for 14 weeks The sample liquefied as an orange liquid within 1 week. Did not receive XRPD analysis data VT-XRPD on C2 No change on heating. Sample melts/decomposes at ~140°C

Example 9 Methanesulfonate (MSA) salt form D of tebipenem pivoxil.

Tebipenem pivoxil (30 mg) was dissolved in t-BuOH (30 vol, 940 μl) with stirring at 50° C., 500 rpm using a magnetic stirrer on a Polar Bear device. The sample was treated with 1 mol-eq. acidic stock solution (1M aq. HBr in THF, 60 μl), then frozen in a dry ice/acetone bath and lyophilized for 16 hours. THF (30 vol, 900 μl) was added to the resulting white solid with stirring at 25° C., 500 rpm. The suspension was heated to 50°C and then cooled to 5°C at 0.2°C/min and kept at 5°C for 12 hours. An aliquot of the suspension was filtered on a 96-well Millipore filter block, dried under vacuum for 10 minutes and analyzed by XRPD (marked as sample ID_EMP_O1). The suspension was stirred at 25°C for 4 hours and then filtered on a 96-well Millipore filter block, dried under vacuum for 10 minutes and analyzed by XRPD.

XRPD analysis of an aliquot of the solid after cooling showed that the material was Form D mesylate. After incubation at 25° C. for 4 hours, XRPD analysis showed a mixture of Form D and Form B mesylate. A sample of pure form D could not be obtained from the scaling experiments, therefore this sample was further characterized, as shown in detail in table. 12. The XRPD for a given crystalline form is shown in FIG. 27.

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Table 12. Tebipenem Pivoxil Form D MSA Solid Phase Characterization Determined from Assays XRPD after chilling, before holding XRPD post exposure DSC TGA Ή-NMR HPL C Storage at 40°C/75% RH and 25°C/97% RH Form D MSA Form a D + form a B MSA Wide endotherm from 30 to 100°C (beginning), 95.4 J/g, acute endotherm at 173.2°C (beginning) 41 J/g. 3.8 wt. % loss and at a temperature from rt to 100°С Corresponds to the structure re, 0.98 equiv. MSA, 0.03 eq. THF 99.6% The sample was converted to Form B after 1 week at 40°C/75% RH. Purity: 99.4% after 1 week at 40°C/75% RH.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.05-1.18 (m, 16H) 1.76 (br t, J=2.78 Hz, 1H) 2.29 (d , J=1.01 Hz, 3H) 2.48-2.52 (m, 1H) 3.28 (dd, J=6.13, 2.34 Hz, 1H) 3.63 (t, J=7 .45 Hz, 2H) 3.89-4.02 (m, 3H)

4.10-4.26 (m, 3H) 4.44 (br s, 1H) 4.66-4.78 (m, 2H) 5.11 (br s, 1H) 5.75 (d, J= 5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10.10 (br s, 1H). The NMR results were consistent with pure tebipenem pivoxil.

The characteristic peaks of the XRPD diffraction pattern are listed in Table 1. 13 and the XRPD spectra are shown in FIG. 27. The DSC and TGA profiles for form B+D are shown in FIG. 28.

Table 13. Peak listing for XRPD pattern D MSA Angle (2-theta°) Intensity (%) 4.3 44.4 7.2 21

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8 15.6 8.7 19 AND 2 9.8 12.6 17.6 12.9 11.8 13.8 11.6 14.5 10.7 16.1 100 16.7 73.1 17.2 31.1 17.5 20.8 17.8 92.3 18.5 64 19.1 54.3 20 48 20.2 54 20.4 29.8 20.7 51.1 21.3 30.3 21.6 17.2 21.8 17.4 22.3 18.2 23.2 27.8 23.7 19.5 24.6 21.1 25.2 26.9 26.8 22 27.5 13.5

Example 10 Crystalline Salt Form B of Tebipenem Pivoxil Hydrobromide (HBr).

Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μl). The counterion (1 M stock solution of HBr in THF) was added in 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 0°C for 2 hours (0.2°C/min) and kept at 0°C for ~2 hours. The resulting slurry was filtered with a fritted filter and air dried on a filter block at ambient conditions for 15 minutes. This material had a purity of 99.4% according to HPLC method A. The XRPD pattern of tebipenem pivoxil HBr crystalline Form B prepared by this method is shown in FIG. 14, and the list of peaks is presented in table. 14.

Salt HBr was also obtained with equivalent purity using the method of the previous paragraph, but with the following changes. Tebipenem pivoxil was dissolved in EtOH (930 µl). A counterion (1 M stock solution of HBr in THF) was added in 1 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. Then the sample was cooled to 5°C for 2 hours (0.2°C/min) and kept at 5°C for approximately 2 hours.

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Table 14. Characteristic angles (2Θ) of salt form B HBr of tebipenem pivoxil Characteristic angle (°) Relative intensity (%) 9.3 50.6 9.5 10 10.7 19.5 12.6 7.2 13.0 17.9 14.0 Yu,1 15.2 6 15.7 6.2 17.6 100 18.7 17.5 19.1 9.9 20.0 79.4 Table 14. Characteristic angles (2Θ) of salt form B HBr of tebipenem pivoxil Characteristic angle (°) Relative intensity(%) 20.4 13.8 20.8 70.3 21.1 14.4 21.9 10.3 22.6 11.8 23.5 27.2 23.7 I,4 24.9 I,6 25.3 I,5 25.5 17.4 25.8 11.7 26.1 18.4 26.5 10.7 26.8 19.9 27.3 17.1 27.6 16 28.4 19 28.8 13.1 29.4 12.1 29.7 15.2 29.9 8.6

DSC profile for the crystalline salt form B of tebipenem pivoxil hydrobromide (Fig.

15) showed a wide melting endotherm starting at 32.9°C with a minimum at 66.3°C and a heat of fusion of 34.1 J/g and an exotherm starting at 186.8°C with a maximum at 190.8 before decomposition. .

The TGA results (also shown in FIG. 15) showed a 1.9% weight loss from room temperature to 100°C. No other thermal events were noted prior to decomposition.

- 32 042386 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.06-1.18 (m, 15H) 3.28 (dd, J=6.19, 2.65 Hz, 1H ) 3.30-3.40 (m, 5H) 3.61-3.69 (m, 2H) 3.90-4.01 (m, 3H) 4.13-4.27 (m, 3H) 4 .41-4.50 (m, 1H) 4.69-4.79 (m, 2H) 5.00-5.01 (m, 1H) 5.11 (br s, 1H) 5.75 (d, J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10.11 (s, 1H). 1HNMR results were consistent with pure tebipenem pivoxil. Approximately 1.04 eq. hydrobromide counterion if the assay was corrected for solvent by TGA. XRPD and HPLC were performed after one week of storage at 40°C and 75% relative humidity. The XRPD pattern was consistent with the pure crystalline form B HBr of tebipenem pivoxil. The sample was 99.2% pure by HPLC.

Example 11 Tebipenem Pivoxil Hydrobromide (HBr) Crystalline Salt Form C.

Tebipenem pivoxil (30 mg) was dissolved in t-BuOH (940 μl) with stirring at 50°C, 500 rpm using a magnetic stirrer on a Polar Bear device. The sample was treated with 1 mol-eq. acidic stock solution (1 M aq. HBr in THF, 60 μl), then frozen in a dry ice/acetone bath and lyophilized for 16 hours. To the resulting white solid was added 1,2-dimethoxyethane (10 vol, 300 µl) with stirring at 50°C. Additional solvent was added to a final volume of 30 vol. (900 µl) to ensure efficient mixing of the suspension. The suspension was cooled to 5°C at 0.2°C/min and kept at 25°C for 72 hours. The resulting suspension was filtered on a 96-well Millipore filter block and dried under vacuum for 15 minutes.

Table 15. Solid phase characterization of HBr Form C of tebipenem pivoxil XRPD Crystal form C Ή-NMR Corresponds to salt form A HBr No residual solvent. HPLC (% AUC) 99.8% DSC No significant thermal events up to exotherms at the beginning decomposition at 179.5°C (Start). TGA 0.5 wt. % loss at temperatures from RT to 140°C, and the beginning of decomposition at 181.8°C. XRPD analysis after storage at 40°C/75% RH for 1 week Invariably according to XRPD (Form C). Peak Intensity decreased, giving suggesting a decrease in crystallinity. HPLC purity after storage = 99.9% Anion IC 0.92 eq. (not corrected for solvent) GVS and XRPD after GVS Didn't carry out

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The characteristic peaks of the XRPD diffraction pattern are presented in Table 1. 16.

Table 16 Peak listing for XRPD form C HBr of tebipenem pivoxil Angle (2-theta°) Intensity % 4.4 72.6 8.7 15.6 9.3 17.1 12 18.4 13.1 21.4 13.6 from 14.2 5.8 15.5 10.4 16.3 29.7 16.5 20.8 17.1 18.1 17.3 21.4 17.6 19.3 18.5 9.6 Table 16 Peak listing for XRPD form C HBr of tebipenem pivoxil Angle (2-theta°) Intensity % 19.3 14.4 19.7 18.7 20.8 26.1 21 21.4 21.3 20.7 21.7 100 22.2 21.3 22.6 22.2 22.8 11.6 23.5 23.1 24 12.1 24.4 6.5 25.2 17.7 25.5 17.4 26.4 13.8 26.7 15.2 27.4 6.5 28.2 14 28.8 21.3 29 11.8 29.5 18.6 29.7 10.4 thirty 16.2 30.5 10.1

1H-NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.18 (m, 15H) 3.28 (dd, J=6.00, 2.46 Hz, 1H) 3.30- 3.39 (m, 5H) 3.64 (t, J=7.52 Hz, 2H) 3.93 (br t, J=7.52 Hz, 3H) 4.11-4.28 (m, 3H ) 4.39-4.51 (m, 1H) 4.66-34 042386

4.80 (m, 2H) 5.11 (br d, J=3.92 Hz, 1H) 5.75 (d, J=5.81 Hz, 1H) 5.88 (d, J=5.81 Hz, 1H) 10.10 (s, 1H). 1P-NMR results were consistent with pure tebipenem pivoxil.

Example 12 Tebipenem Pivoxil Hydrobromide (HBr) Crystalline Salt Form D.

Tebipenem pivoxil (2.5 g) was dissolved in a minimum volume of t-BuOH (25 vol., 62.5 ml) with stirring at 50°C, 600 rpm using a magnetic stirrer on a Polar Bear device. The sample was treated with 1 mol-eq. acidic stock solution (1M HBr aq. in THF, 4 ml), then frozen in a dry ice/acetone bath and lyophilized for 16 hours. The resulting white solid was crushed with a pestle and mortar and dried in a vacuum oven at 60° C. for 4 hours. ., 15 ml) at 50°C, 500 rpm for 30 minutes. Then the samples were cooled from 50 to 5°C at 0.2°C/min, and then stirred at 25°C for 24 hours. The resulting suspension was filtered on a Buchner funnel and dried under vacuum for 20 minutes.

Table 17. Tebipenem Pivoxil HBr Form D Solid Phase Characterization XRPD Form D Ή-NMR Corresponds to salt form B NVg No residual solvent. HPLC (%, AUC) Method B 98.8% DSC Wide endotherm at RT to 100°C (37.4°C, onset, 5 J/g). Decomposition exotherm at 162.8°C (beginning). TGA 0.5 wt. % loss at temperatures from RT to 100°C. There are no other events before decomposition. Analysis of XRPD after storage at 40°C/75% RH or 25°C/97% RH for 1 week Conversion to form B HBr within 1 week at 25°C/97% RH, and liquefaction at 40°C/75% RH within 1 week. AnionIC 0.97 eq. Vg KF 0.2% water GVS and XRPD after GVS The sample showed initial absorption, component 3.0 wt. %, 40 to 90% RH, then reversible absorption and loss. Total 4.0-4.5 wt. % absorption from 0 to 90% RH. XRPD after GVS showcased blend form B and form D HBg VT-XRPD Shape has not changed during or after VT-XRPD VH-XRPD Shape has not changed during or after VH-XRPD

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The characteristic peaks of the XRPD diffraction pattern are listed in Table 1. 18 and the XRPD pattern is shown in FIG. 23.

Table 18. List of peaks for diffractograms XRPD form D HBr Angle (2-theta°) Intensity (%) 4.4 61.7 8.3 9.1 8.6 27 8.8 21.1 10.2 5.4 10.9 5.8 13.3 15.1 14.2 36.9 15.6 5.5 16.3 34 16.7 14.4 17.1 25.9 17.3 13.5 17.8 12.7 18 15.4 18.3 19 18.8 29.8 20.7 24.6 21 30.3 21.7 100 22.3 40.3 23 9.7 23.4 9.3 23.9 20.2 24.6 9.4 24.9 12.5 25.2 from 26.1 17.7 26.5 14.2 26.8 7.5 27.3 9.4 27.5 9.8 28.6 21.9 28.9 16.5 29.7 10.8

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.04-1.21 (m, 15H) 3.28 (dd, J=5.94, 2.27 Hz, 1H) 3, 30-3.52 (m, 4H) 3.65 (t, J=7.52 Hz, 2H) 3.88-4.01 (m, 3H) 4.19 (br dd, J=9.22, 2.02 Hz, 3H) 4.45 (br d, J=5.18 Hz, 1H) 4.66-4.81 (m, 2H) 4.95-5.28 (m, 1H) 5.75 (d, J=5.81 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10.11 (br s, 1H). 1H-NMR results were consistent with pure tebipenem pivoxil.

Example 13 Crystalline Salt Form A of edisylate (EDSA) of tebipenem pivoxil.

Tebipenem pivoxil (30 mg) was dissolved in MeCN (320 µl). The counterion (1 M stock solution of ethanedisulfonic acid in THF) was added in 0.5 mol-eq. and stirred at 25° C., 500 rpm with a magnetic stirrer in a Polar Bear device for 20 minutes. The sample was then cooled to

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5°C for 2 hours (0.25°C/min) and kept at 5°C for ~1 hour. A precipitate was obtained which was filtered with a fritted filter and air dried on a filter block under ambient conditions for 15 minutes. The XRPD pattern of tebipenem pivoxil edisylate Form A crystal obtained by this method is shown in FIG. 16, and the list of peaks is presented in table. 19. The crystalline material was found to be 94.6% pure by HPLC.

Table 19. Characteristic angles (2Θ) of tebipenem pivoxil edisylate salt Form A Characteristic angle (°) Relative intensity (%) 4.1 100 5.0 80.7 7.7 20.9 8.2 52.8 8.5 23.4 9.5 21.2 Yu,1 27.7 13.1 16.8 13.5 15.1 15.4 22.9 16 22 16.9 27 17.3 32.1 18 37.4 19.1 32.1 20.3 47.6 20.7 46.2 21.2 62.9 22.7 16.6 23.1 25.1 24.5 23.3 25.7 24.6 27.3 31.4 28.8 20.3

The DSC profile for the crystalline salt form A of tebipenem pivoxil edisylate (Fig. 17) shows a wide melting endotherm starting at 56.3°C with a minimum at 79.3°C and a melting enthalpy of 69 J/g and a small endotherm starting at 144, 5°C with a minimum at 157.5°C and a melting enthalpy of 14 J/g.

The TGA results for tebipenem pivoxil edisylate salt form A (also shown in FIG. 17) showed a 4.0% weight loss from room temperature to 160°C. No other thermal events were noted prior to decomposition.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.05-1.19 (m, 15H) 2.01-2.08 (m, 1H) 2.07 (s, 1H) 2 .61 (s, 2H) 3.27 (dd, J=6.19, 2.78 Hz, 1H) 3.34 (s, 17H) 3.62 (t, J=7.52 Hz, 2H) 3 .89-4.01 (m, 3H) 4.09-4.24 (m, 3H) 4.39-4.49 (m, 1H) 4.70 (td, J=8.87, 4.36 Hz, 2H) 5.11 (d, J=5.18 Hz, 1H) 5.75 (d, J=5.94 Hz, 1H) 5.88 (d, J=5.94 Hz, 1H) 10 .12 (br s, 1H). 1H-NMR results were consistent with pure tebipenem pivoxil. Approximately 0.47 equivalents of edisylate counterion and 0.24 equivalents of MeCN solvent were observed. After three days of storage at 40° C. and 75% relative humidity, the sample was found to have liquefied.

Example 14 Preparative synthesis of HBr tebipenem pivoxil.

In a 20 L reactor flask equipped with a thermometer and an addition funnel and a mechanical stirrer immersed in an empty tube, tebipenem pivoxil (1.00 kg, 2.01 mol, 1.0 eq., 99.5% pure according to HPLC ) was dissolved in 8.0 L of acetonitrile. The solution (completely transparent) is moved

Claims (3)

were sieved at rt. In a separate round-bottom flask, a solution of HBr in acetonitrile was prepared. 1.5 L of acetonitrile was stirred into RBF, then cooled in an ice bath. At 5° C., 230 ml of a solution of HBr (48%, aq.) (1.0 eq. HBr relative to tebipenem pivoxil) was added at such a rate that the temperature did not exceed 10° C. (~15 min). The HBr solution (T adjusted to 0° C. prior to addition) was added at a rate of 33 ml min-1 (required only 1 hour) to the tebipenem pivoxil solution from a 1 L addition funnel (funnel topped up when added). After adding approximately 0.5 L of HBr solution, precipitation was evident. The mixture was cooled to 5°C and stirred for 1 h. The mixture was filtered through a large P3 glass filter and the precipitate was washed with 1 L of acetonitrile at rt. The filter cake was dried on the filter for 30 min, then transferred to a tray and dried under vacuum with blowing N2. Tebipenem pivoxil hydrobromide (0.970 g, 1.68 mol, 83.6% yield, 99.2% purity by HPLC) was determined to be dry by NMR (not shown) and packaged in large 2 L vials and stored at 2-85°C. Example 15 Stability Studies The results of salt analysis using tebipenem pivoxil free base are summarized in Table 1. 20. Table 20 Results of Salt Analysis Using Free Base Salt Malat Maleate Ezilat Example No. Example 5 Example 4 Example 1 HPLC(AUC) 97.3% (method A) 99.3% (method B) 99.3% (method A) 99.8% (method B) 99.0% (method A) 99.8% (method B) XRPD and HPLC analyzes after storage at 40°C/75% RH 1 week Transition to liquid state, orange liquid Form B MAE 78.6% (Method A) Form A ESA (yellow solid) 80.7% (method A) Characterization of the edisylate salt of tebipenem pivoxil obtained from free form assays in acetonitrile is summarized in Table 1. 21. Table 21 Characterization of tebipenem pivoxil edisylate salt derived from free form assays in acetonitrile HPLC (%, AUC), Method A 94.6% XRPD analysis after storage at 40°C/75% RH 1 week Transition to a liquid state (within 3 days) Table22. Salt reanalysis results using free base in acetonitrile Example No. Example 4 Example 2 Example 1 XRPD Form B maleate Form A ketoglutarate Form A esilata XRPD and HPLC analysis after storage at 40°C/75% RH for 1 week Form B maleate 90.2% (method A) Transition to liquid state Liquidization/Resin While the subject matter of the present invention has been described with reference to exemplary embodiments, those skilled in the art will appreciate that various changes may be made and elements may be substituted for their equivalents without departing from the scope of the disclosure. In addition, many modifications can be made to adapt a particular situation or material to the principles of the present invention without deviating from their main scope. Thus, the present invention is not intended to be limited to the specific embodiments disclosed, but to include all embodiments falling within the scope of the appended claims. CLAIM 1. Crystalline salt form of tebipenem pivoxil hydrobromide (Form B) characterized by an XRPD diffraction pattern obtained using a Cu Ka source that contains peaks at 2Θ angle values of 9.3, 13.0, 17.6, 20.8, 25.8 and 26.1 +/-0.2 degrees 2Θ and/or 10.7, 14.0, 18.7, 20.0, 20.4 and 23.5 +/-0.2 degrees 2θ. 2. A crystalline salt form of tebipenem pivoxil hydrobromide according to claim 1, further characterized by a DSC profile as shown in FIG. 15. 3. Crystalline salt form of tebipenem pivoxil hydrobromide according to claim 1, additionally ha- -