Crystalline forms of a monobactam

Abstract

This disclosure relates to the crystalline hydrate forms of (S)-2-((R)-6-(N-((1s,3S)-3-amino-cyclobutyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, including crystalline hydrate form A, crystalline hydrate form B and crystalline hydrate form D, which are useful as antibiotic agents for the treatment of bacterial infections, such as bacterial infections caused by gram-negative bacteria, including strains that are multidrug resistant.

Description

CRYSTALLINE FORMS OF A MONOBACTAMCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Nos. 63 / 710,957, filed October 23, 2024; the disclosure of which is incorporated herein by reference in its entirety.FIELD

[0002] This disclosure relates to crystalline forms, or polymorphs, of (S)-2-((R)-6-(N-((ls,3S)-3-amino-cyclobutyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo- 1 -(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, and hydrates and salts thereof, which is a potent monobactam compound. This novel compound, and the crystalline forms thereof, are useful as antibiotic agents for the treatment of bacterial infections. This disclosure further concerns pharmaceutical compositions comprising the crystalline forms of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-I-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy / -propanoic acid, and hydrates and salts thereof, which are antibiotics effective against a broad range of gram-negative bacteria, and may be useful as therapeutic agents for clinical treatment of various infections caused by gram-negative bacteria, including strains that are multidrug resistant.BACKGROUND

[0003] The introduction of antibiotics for treatment of bacterial infections is one of the great medical achievements of the 20thcentury'. However, bacteria resistant to multiple antibiotics have begun to emerge throughout the world, threatening the effectiveness of antibiotic therapy. [ -lactams, including carbapenems, cephalosporins, penicillins, and monobactams, are the most widely used antibiotics for treatment of serious bacterial infections, however, resistance to f>-lactams has emerged. For most Gram-negative bacteria, this resistance is primarily driven by the expression of P-lactamases, enzymes that hydrolyze [3-lactam compounds. There are 4 different classes of P-lactamases (A, B, C, and D) capable of hydrolyzing overlapping but distinct subsets of P-lactams (Drawz and Bonomo, Clin. Micro. Rev., 2010, 23:160-201). While the class B P-lactamases, also know n as metallo P-lactamases (MBLs), are not the most prevalent P-lactamases found in the clinic, the frequency and distribution of their expression is on the rise and represent a significant medical threat because (i) MBLs have the ability to hydrolyze all P-lactams exceptmonobactams, and (ii) unlike the class A and C 0-lactamases, there are no inhibitors available for the MBLs.

[0004] Monobactams, including (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l -(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, are inherently resistant to hydrolysis by metallo 0-lactamases, and may be useful for inhibiting the growth of Gramnegative bacterial strains, including but not limited to, Pseudomonas, Klebsiella and Acinetobacter strains, including Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii, and / or for treating or preventing the clinical manifestations thereof in a patient.

[0005] WO 2023 / 091438 describes monobactam compounds that are potent antibiotics useful for the treatment of bacterial infections. Specifically disclosed in WO 2023 / 091438 is (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l -(sulfooxy )-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-propanoic acid, and pharmaceutically acceptable salts thereof.

[0006] However, there is no specific disclosure in WO 2023 / 091438 of crystalline forms or crystalline hydrate forms of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l -(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid.SUMMARY

[0007] The present disclosure is concerned with crystalline forms A, B and D of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2.2-dimethyl-4-oxo-l -(sulfooxy )-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-propanoic acid. In particular, the present disclosure is concerned with crystalline hydrate forms A, B and D of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-propanoic acid.

[0008] The crystalline forms of the present disclosure exhibit pharmaceutic advantages over the previously disclosed neutral zwitterion, trifluoracetic acid and formic acid salts of (S)-2-((R)-6-(N-((ls,3S)-3-amino-cyclobutyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-propanoic acid, such as greater purity and / or physical stability, which are advantageous in the preparation of a pharmaceutical drug product containing the compound of formula I.

[0009] In particular, the crystal 1 ine hydrate form A of the compound of formula I exhibits physical stability in environments with low relative humidity between about 0 % to about 33% relative humidity (RH). The crystalline hydrate form B of the compound of formula I exhibits physical stability, and is the preferred form, at a relative humidity7between about 33% to less than about 41% relative humidity (RH). Crystalline hydrate form D of the compound of formula I unexpectedly exhibits greater physical stability7in a higher humidity7environment of greater than or equal to about 55 % relative humidity. As a result, crystalline hydrate form D has increased stability to greater stress, high temperatures and higher humidity, and also exhibits the physical stability required for ease of processing and handling rendering it suitable for use in manufacturing various dosage forms of the compound of formula I.

[0010] This disclosure also concerns pharmaceutical compositions containing crystalline forms of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, and pharmaceutical compositions containing crystalline hydrate forms of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l -(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, as well as methods for using these crystalline forms as antibiotics, in particular for the treatment of bacterial infections.BRIEF DESCRIPTION OF THE FIGURES

[0011] FIG. 1 is a X-ray diffraction pattern of the crystalline hydrate form A of the compound of formula I.

[0012] FIG. 2 is a thermogravimetric analysis (TGA) curve and a differential scanning calorimetry (DSC) curve of the crystalline hydrate form A of compound of formula I.

[0013] FIG. 3 is a X-ray diffraction pattern of the crystalline hydrate form B of compound of formula I.

[0014] FIG. 4 is a thermogravimetric analysis (TGA) curve of the crystalline hydrate form B of compound of formula I.

[0015] FIG. 5 is a differential scanning calorimetry (DSC) curve of the crystalline hydrate form B of compound of formula I.

[0016] FIG. 6 is a X-ray diffraction pattern of the crystalline hydrate form D of compound of formula I.

[0017] FIG. 7 is a thermogravimetric analysis (TGA) curve of the cry stalline hydrate form D of compound of formula I.

[0018] FIG. 8 is a differential scanning calorimetry (DSC) curve of the crystalline hydrate form D of compound of formula I.

[0019] FIG 9 is the phase boundary map for the crystalline hydrate forms A, B, and D with respect to relative humidity'.DETAILED DESCRIPTION

[0020] This disclosure provides crystalline forms of (S)-2-((R)-6-(N-((ls,3S)-3-amino-cyclobutyl)carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (the compound of formula I), or a hydrate and / or salt thereof, which have the following structure:

[0021] In particular, this disclosure relates to cry stalline hydrate forms A, B and D of the compound of formula I, which have the following structure.

[0022] Also provided is a particular drug substance that comprises the crystalline hydrate forms A, B and D of the compound of formula I as described herein. In one embodiment is provided a drug substance that comprises a crystalline hydrate form A, form B or form D of the compound of formula I present in a detectable amount. By “drug substance’' is meant the active pharmaceutical ingredient. The presence of crystalline hydrate forms A, B and D in a drug substance can be detected by physical methods known to those of ordinary skill in the art, such as X-ray powder diffraction, TG, and carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectroscopy. The amount of crystalline hydrate form A, Band D of the compound of formula 1 in the drug substance can be quantified by the use of physical methods such as X-ray powder diffraction, solid-state carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance spectroscopy, DSC, TGA, IR spectroscopy, and / or Raman spectroscopy.

[0023] In another embodiment, the crystalline form of the compound of formula I is crystalline hydrate form A of the compound of formula I. In another embodiment, the crystalline form of the compound of formula I is crystalline hydrate form B of the compound of formula I. In another embodiment, the crystalline form of the compound of formula I is a crystalline hydrate form D of the compound of formula I.

[0024] In another embodiment, the compound of formula I comprises a detectable amount of a crystalline form of the compound of formula I. In a class of this embodiment, the compound of formula I comprises a detectable amount of a crystalline hydrate form of the compound of formula I. In another class of this embodiment, the compound of formula I comprises a detectable amount of the crystalline hy drate form A of the compound of formula I. In another class of this embodiment, the compound of formula I comprises a detectable amount of the cry stalline hydrate form B of the compound of formula I. In another class of this embodiment, the compound of formula I comprises a detectable amount of the crystalline hydrate form D of the compound of formula I.

[0025] In another embodiment, the compound of formula I comprises about 1% to about 100% by weight of a crystalline form of the compound of formula I. In a class of this embodiment, the compound of formula I comprises about 1% to about 100% by weight of a crystalline hydrate form of the compound of formula I. In another class of this embodiment, the compound of formula 1 comprises about 1% to about 100% by weight of the crystalline hydrate form A of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 1% to about 100% by weight of the crystalline hydrate form B of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 1% to about 100% by weight of the crystalline hydrate form D of the compound of formula I.

[0026] In another embodiment, the compound of formula I comprises about 10% to about 100% by weight of a cry stalline form of the compound of formula I. In a class of this embodiment, the compound of formula I comprises about 10% to about 100% by weight of a crystalline hydrate form of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 10% to about 100% by weight of the crystalline hydrate form A of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 10% to about 100% by weight of the crystalline hydrate form B of thecompound of formula I. In another class of this embodiment, the compound of formula 1 comprises about 10% to about 100% by weight of the crystalline hydrate form D of the compound of formula I.

[0027] In another embodiment, the compound of formula I comprises about 25% to about 100% by weight of a crystalline form of the compound of formula I. In a class of this embodiment, the compound of formula I comprises about 25% to about 100% by weight of a crystalline hydrate form of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 25% to about 100% by weight of the crystalline hydrate form A of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 25% to about 100% by weight of the crystalline hydrate form B of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 25% to about 100% by weight the cry stalline hydrate form D of the compound of formula I.

[0028] In another embodiment, the compound of formula I comprises about 50% to about 100% by weight of a crystalline form of the compound of formula I. In a class of this embodiment, the compound of formula I comprises about 50% to about 100% by weight of a crystalline hydrate form of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 50% to about 100% by weight of the crystalline hydrate form A of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 50% to about 100% by weight of the cry stalline hydrate form B of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 50% to about 100% by weight of the crystalline hydrate form D of the compound of formula I.

[0029] In another embodiment, the compound of formula I comprises about 75% to about 100% by weight of a cry stalline form of the compound of formula I. In a class of this embodiment, the compound of formula I comprises about 75% to about 100% by weight of a crystalline hydrate form of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 75% to about 100% by weight of the crystalline hydrate form A of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 75% to about 100% by weight of the crystalline hydrate form B of the compound of formula I. In another class of this embodiment, the compound of formula I comprises about 75% to about 100% by weight of the crystalline hydrate form D of the compound of formula I.

[0030] In another embodiment, the compound of formula I comprises substantially all by weight of a crystalline form. In a class of this embodiment, the compound of formula I comprises substantially all by weight of a crystalline hydrate form. In another class of this embodiment, the compound of formula I comprises substantially all by weight of the crystalline hydrate form A of the compound of formula I. In another class of this embodiment, the compound of formula I comprises substantially all by weight of the crystalline hydrate form B of the compound of formula I. In another class of this embodiment, the compound of formula I comprises substantially all by weight of the crystalline hydrate form D of the compound of formula I.

[0031] In another embodiment, about 5% to about 100% by weight of a crystalline form is present in the drug substance. In a class of this embodiment, about 5% to about 100% by weight of a cry stal I i ne form is present in the drug substance. In another class of this embodiment, about 5% to about 100% by weight of the crystalline hydrate form A of the compound of formula I is present in the drug substance. In another class of this embodiment, about 5% to about 100% by weight of the crystalline hydrate form B of the compound of formula I is present in the drug substance. In another class of this embodiment, about 5% to about 100% by weight of the cry stalline hydrate form D of the compound of formula I is present in the drug substance.

[0032] In another embodiment, about 10% to about 100% by weight of a crystalline form is present in the drug substance. In a class of this embodiment, about 10% to about 100% by weight of a crystalline form is present in the drug substance. In another class of this embodiment, about 10% to about 100% by weight of the cry stalline hydrate form A of the compound of formula I is present in the drug substance. In another class of this embodiment, about 10% to about 100% by¬ weight of the crystalline hydrate form B of the compound of formula I is present in the drug substance. In another class of this embodiment, about 10% to about 100% by weight of the crystalline hydrate form D of the compound of formula I is present in the drug substance.

[0033] In another embodiment, about 25% to about 100% by w eight of a crystalline form is present in the drug substance. In a class of this embodiment, about 25% to about 100% by weight of a crystalline hydrate form is present in the drug substance. In another class of this embodiment, about 25% to about 100% by weight of the crystalline hydrate form A of the compound of formula I is present in the drug substance. In another class of this embodiment, about 25% to about 100% by weight of the cry stalline hydrate form B of the compound of formula I is present in the drug substance. In another class of this embodiment, about 25% to about 100% by weight of the crystalline hydrate form D of the compound of formula I is present in the drug substance.

[0034] In another embodiment, about 50% to about 100% by weight of a crystalline form is present in the drug substance. In a class of this embodiment, about 50% to about 100% by weight of a crystalline hydrate form is present in the drug substance. In another class of this embodiment, about 50% to about 100% by weight of the crystalline hydrate form A of the compound of formula I is present in the drug substance. In another class of this embodiment, about 50% to about 100% by weight of the crystalline hydrate form B of the compound of formula I is present in the drug substance. In another class of this embodiment, about 50% to about 100% by weight of the crystalline hydrate form D of the compound of formula I is present in the drug substance.

[0035] In another embodiment, about 75% to about 100% by weight of crystalline form is present in the drug substance. In a class of this embodiment, about 75% to about 100% by weight of cry stalline form is present in the drug substance. In another class of this embodiment, about 75% to about 100% by weight of the crystalline hydrate form A of the compound of formula I is present in the drug substance. In another class of this embodiment, about 75% to about 100% by weight of the crystalline hydrate form B of the compound of formula I is present in the drug substance. In another class of this embodiment, about 75% to about 100% by weight of the crystalline hydrate form D of the compound of formula I is present in the drug substance.

[0036] In another embodiment, substantially all of the drug substance is a crystalline form of the present disclosure, i.e., the drug substance is substantially a crystalline form of the compound of formula I. In a class of this embodiment, substantially all of the drug substance is a crystalline hydrate form of the present disclosure, i.e., the drug substance is substantially a cry stalline hydrate form of the compound of formula I. In another class of this embodiment, substantially all of the drug substance is the crystalline hydrate form A of the compound of formula 1. In another class of this embodiment, substantially all of the drug substance is the crystalline hydrate form B of the compound of formula I. In another class of this embodiment, substantially all of the drug substance is the cry stalline hydrate form D of the compound of formula I. In another embodiment, the crystalline form of the compound of formula I is crystalline form A of the compound of formula I, crystalline form B of the compound of formula I or crystalline form D of the compound of formula I, or a mixture thereof. In another embodiment, the cry stalline form of the compound of formula I is cry stalline hydrate form A of the compound of formula I, crystalline hydrate form B of the compound of formula I or crystalline hydrate form D of the compound of formula I, or a mixture thereof.

[0037] In another embodiment, the crystalline form of the compound of formula I is crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, orcrystalline form D of the compound of formula I. In another embodiment, the crystalline form of the compound of formula I is cry stal line hydrate form A of the compound of formula I, cry stalline hydrate form B of the compound of formula I, or cry stalline hydrate form D of the compound of formula I.

[0038] In another embodiment of the present disclosure, the compound of formula I is crystalline hydrate form A of the compound of formula I, which is further described below. In a class of this embodiment is provided a particular drug substance that comprises at least one of crystalline hydrate form A, B or D of the compound of formula I. The presence of crystalline hydrate form A, B or D in a drug substance can be detected by physical methods known to those of ordmary skill in the art, such as X-ray powder drffraction (XRPD), single crystal X-ray diffraction, TG, DSC and carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectroscopy.

[0039] In another class of this embodiment, crystalline hydrate form A of the compound of formula I is obtained by formation of wet slurry isolated from stirring the compound of formula I in pH 4 acetate buffer. In another class of this embodiment, crystalline hydrate form A of the compound of formula I is obtained by formation of wet slurry' isolated from stirring the compound of formula I in 50 mM pH 4 sodium acetate buffer. In another class of this embodiment, crystalline hydrate form A of the compound of formula I is obtained by drying of a slurry' of the compound of formula I from water to a relative humidity between 0% to about 33 % RH. In another class of this embodiment, crystalline hydrate form A of the compound of formula I is obtained by formation of wet slurry' isolated from stirring the compound of formula I in pH 4 acetate buffer, and then drying of slurry from water to relative humidity between 0% to about 33 % RH. In another class of this embodiment, crystalline hydrate form A of the compound of formula I is obtained by formation of wet sluny' isolated from stirring the compound of formula I in 50 mM pH 4 sodium acetate buffer, and then drying of slurry' from water to relative humidity between 0% to about 33 % RH.

[0040] In another class of this embodiment is provided a particular drug substance that comprises crystalline hydrate form A of the compound of formula I. The presence of crystalline hydrate form A in a drug substance can be detected by physical methods known to those of ordinary skill in the art, such as X-ray powder diffraction (XRPD), single crystal X-ray diffraction. TG, DSC, and carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectroscopy.

[0041] In another class of this embodiment, crystalline hydrate form A of the compound of formula I is characterized by an X-ray powder diffraction pattern measured using CuKa radiationselected from: about 10.99, about 11.89, about 14.65, about 15.6, about 16.85, about 20.68, and about 22.19 °20. The crystalline hydrate form A of the compound of formula I exhibited characteristic diffraction peaks corresponding to d-spacings of about 14.65, about 15.65, and about 22.19 angstroms. The crystalline hydrate form A of the compound of formula I was further characterized by the d-spacings of about 11.89, about 16.85, and about 20.68 angstroms. The crystalline hydrate form A of the compound of formula I was even further characterized by the d-spacing of 10.99 angstroms.

[0042] In another class of this embodiment is provided a composition comprising crystalline hydrate form A of the compound of formula I wherein about 100% of the compound of formula I is crystalline hydrate form A of the compound of formula I. In another class of this embodiment are provided compositions comprising the compound of formula I, wherein about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%. about 88%, about 87%, about 86%, about 85%, about 84%, about 83%, about 82%, about 81%. about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%, about 64%, about 63%, about 62%, about 61%, about 60%, about 59%, about 58%, about 57%, about 56%, about 55%, about 54%, about 53%, about 52%, about 51%, about 50%. about 49%. about 48%, about 47%, about 46%, about 45%. about 44%, about 43%, about 42%, about 41%, about 40%, about 39%, about 38%, about 37%, about 36%, about 35%, about 34%, about 33%, about 32%, about 31%, about 30%, about 29%, 28%, 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, about 16%. about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% of the compound of formula I is in the form of crystalline hydrate form A of the compound of formula I.

[0043] In another class of this embodiment, about 10% to about 100% of the compound of formula I in the composition is crystalline hydrate form A of the compound of formula I. In a subclass of this class, about 25% to about 98%, from about 50% to about 96%, from about 75% to about 95%, from about 90% to about 94%, or about 92% is crystalline hydrate form A of the compound of formula I.

[0044] In another class of this embodiment is provided crystalline hydrate form A of the compound of formula I of 100%, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%,56%. 55%. 54%. 53%. 52%. 51%. 50%. 49%. 48%. 47%. 46%. 45%. 44%. 43%. 42%. 41%. 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% purity.

[0045] In another class of this embodiment, crystalline hydrate form A of the compound of formula I is characterized by an X-ray powder diffraction pattern substantially as shown in Fig.1.

[0046] In another class of this embodiment, crystalline hydrate form A of the compound of formula I is characterized by a TGA substantially as shown in Fig. 2.

[0047] In another class of this embodiment, crystalline hydrate form A of the compound of formula I is characterized by a DSC substantially as shown in Fig. 2.

[0048] Another embodiment of this disclosure provides crystalline hydrate form B of the compound of formula I, which is further described below.

[0049] In a class of this embodiment, crystalline hydrate form B of the compound of formula I is obtained by freeze drying, or lyophilizing, the wet slurry formed by stirring the compound of formula I in pH 4 acetate buffer. In another class of this embodiment, crystalline hydrate form B of the compound of formula I is obtained by freeze drying, or lyophilizing, the wet slurry formed by stirring the compound of formula I in 50 mM pH 4 sodium acetate buffer. In another class of this embodiment, cry stal 1 ine hydrate form B of the compound of formula I is obtained from a wet slurry of the compound of formula I in ethyl acetate and isopropanol. In another class of this embodiment, cry stalline hydrate form B of the compound of formula I is obtained from dry ing a slurry’ of the compound of formula I in ethyl acetate and isopropanol.

[0050] In another class of this embodiment is provided a particular drug substance that comprises crystalline hydrate form B of the compound of formula I. The presence of crystalline hydrate form B in a drug substance can be detected by physical methods known to those of ordinary skill in the art, such as X-ray powder diffraction (XRPD), single crystal X-ray diffraction. TG, DSC, and carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectroscopy.

[0051] In another class of this embodiment, crystalline hydrate form B of the compound of formula I is characterized by an X-ray poyvder diffraction pattern measured using CuKa radiation selected from: about 9.96, about 12.08, about 14.82, about 15.77, about 17.10, about 18.47, about 20.79, about 22.29, about 23.69, about 26.63, and about 32.81 °20.

[0052] The crystalline hydrate form B of the compound of formula I exhibited characteristic diffraction peaks corresponding to d-spacings of about 14.82, about 15.77, and about 17.10angstroms. The crystalline hydrate form B of the compound of formula 1 was further characterized by the d-spacings of about 18.47, about 20.79, and about 22.29 angstroms. The crystalline hydrate form B of the compound of formula I was even further characterized by the d-spacings of about 12.08, and about 23.69 angstroms.

[0053] In another class of this embodiment is provided a composition comprising crystalline form B of the compound of formula I wherein about 100% of the compound of formula I is crystalline hydrate form B of the compound of formula I. In another class of this embodiment are provided compositions comprising the compound of formula I, wherein about 99%, about 98%, about 97%. about 96%, about 95%, about 94%, about 93%, about 92%. about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, about 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%. about 64%, about 63%, about 62%, about 61%, about 60%. about 59%, about 58%, about 57%. about 56%, about 55%, about 54%, about 53%, about 52%. about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, about 45%, about 44%, about 43%, about 42%, about 41%, about 40%, about 39%, about 38%, about 37%, about 36%, about 35%, about 34%, about 33%, about 32%, about 31%, about 30%, about 29%, 28%, 27%, about 26%, about 25%, about 24%. about 23%, about 22%, about 21%, about 20%. about 19%. about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% of the compound of formula I is in the form of cry stalline hy drate form B of the compound of formula I.

[0054] In another class of this embodiment, about 10% to about 100% of the compound of formula I in the composition is crystalline hydrate form B of the compound of formula I. In a subclass of this class, about 25% to about 98%, from about 50% to about 96%, from about 75% to about 95%, from about 90% to about 94%, or about 92% is crystalline hydrate form B of the compound of formula I.

[0055] In another class of this embodiment is provided crystalline hydrate form B of the compound of formula I of 100%, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%. 70%, 69%. 68%. 67%. 66%. 65%. 64%. 63%. 62%. 61%. 60%. 59%. 58%. 57%. 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%,24%. 23%. 22%. 21%. 20%. 19%. 18%. 17%. 16%. 15%. 14%. 13%. 12%. 11%. 10%. 9%, 8%.7%, 6%, 5%, 4%, 3%, 2%, or 1% purity.

[0056] In another class of this embodiment, crystalline hydrate form B of the compound of formula I is characterized by an X-ray powder diffraction pattern substantially as shown in Fig.3.

[0057] In another class of this embodiment, crystalline hydrate form B of the compound of formula I is characterized by a TGA substantially as shown in Fig. 4.

[0058] In another class of this embodiment, crystalline hydrate form B of the compound of formula I is characterized by a DSC substantially as shown in Fig. 5.

[0059] Another embodiment of this disclosure provides crystalline hydrate form D of the compound of formula I, which is further described below’.

[0060] In a class of this embodiment, crystalline hydrate form D of the compound of formula I is obtained by drying a slurry’ of crystalline hydrate form A of the compound of formula I and crystalline hydrate form B of the compound of formula I in pH 4 acetate buffer. In another class of this embodiment, crystalline hydrate form D of the compound of formula I is obtained by drying a slurry’ formed by stirring the crystalline hydrate form A of the compound of formula I and crystalline hydrate form B of the compound of fonwula I in 50 mM pH 4 sodium acetate buffer. In another class of this embodiment, crystalline hydrate form D of the compound of formula I is obtained by drying a slurry formed by stirring the crystalline hydrate form A of the compound of formula I and crystalline hydrate form B of the compound of formula I in 50 mM pH 4 sodium acetate buffer to a relative humidity >55 % RH.

[0061] In another class of this embodiment is provided a particular drug substance that comprises crystalline hydrate form D of the compound of formula 1. The presence of crystalline hydrate form D in a drug substance can be detected by physical methods known to those of ordinary’ skill in the art, such as X-ray powder diffraction (XRPD), single cry stal X-ray diffraction, TG, DSC, and carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectroscopy.

[0062] In another class of this embodiment, crystalline hydrate form D of the compound of formula I is characterized by an X-ray powder diffraction pattern measured using CuKa radiation selected from: about 8.03, about 9.23, about 10.77, about 13.55, about 14.62, about 17.64, about 20.02, about 21.59, and about 26.65 °20.

[0063] The crystalline hydrate form D of the compound of formula I exhibited characteristic diffraction peaks corresponding to d-spacings of about 10.77, about 14.62, and about 20.02 angstroms. The cry stalline hydrate form D of the compound of formula I was furthercharacterized by the d-spacings of about 8.03, about 13.55, and about 17.64 angstroms. The crystalline hydrate form D of the compound of formula I was even further characterized by the d-spacings of about 21.59, and about 26.65 angstroms. The crystalline hydrate form D of the compound of formula I was even further characterized by the d-spacing of about 9.23 angstroms.

[0064] In another class of this embodiment is provided a composition comprising crystalline form D of the compound of formula I wherein about 100% of the compound of formula I is cry stal I i n e hydrate form D of the compound of formula I. In another class of this embodiment are provided compositions comprising the compound of formula I, wherein about 99%, about 98%, about 97%. about 96%, about 95%, about 94%, about 93%, about 92%. about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, about 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%. about 64%, about 63%, about 62%, about 61%, about 60%. about 59%, about 58%, about 57%. about 56%, about 55%, about 54%, about 53%, about 52%. about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, about 45%, about 44%, about 43%, about 42%, about 41%, about 40%, about 39%, about 38%, about 37%, about 36%, about 35%, about 34%, about 33%, about 32%, about 31%, about 30%, about 29%, 28%, 27%, about 26%, about 25%, about 24%. about 23%, about 22%, about 21%, about 20%. about 19%. about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% of the compound of formula I is in the form of cr stalline hydrate form D of the compound of formula I.

[0065] In another class of this embodiment, about 10% to about 100% of the compound of formula I in the composition is crystalline hydrate form D of the compound of formula I. In a subclass of this class, about 25% to about 98%, from about 50% to about 96%, from about 75% to about 95%, from about 90% to about 94%, or about 92% is crystalline hydrate form D of the compound of formula I.

[0066] In another class of this embodiment is provided crystalline hydrate form D of the compound of formula I of 100%, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%. 70%, 69%. 68%. 67%. 66%. 65%. 64%. 63%. 62%. 61%. 60%. 59%. 58%. 57%. 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%,24%. 23%. 22%. 21%. 20%. 19%. 18%. 17%. 16%. 15%. 14%. 13%. 12%. 11%. 10%. 9%, 8%.7%, 6%, 5%, 4%, 3%, 2%, or 1% purity.

[0067] In another class of this embodiment, crystalline hydrate form D of the compound of formula I is characterized by an X-ray powder diffraction pattern substantially as shown in Fig.6.

[0068] In another class of this embodiment, crystalline hydrate form D of the compound of formula I is characterized by a TGA substantially as shown in Fig. 7.

[0069] In another class of this embodiment, crystalline hydrate form D of the compound of formula I is characterized by a DSC substantially as shown in Fig. 8.

[0070] The crystalline forms and crystalline hydrate forms A, B and D of the compound of formula I of the present disclosure are potent antibiotics useful for the prevention or treatment of bacterial infections, wherein the bacteria infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.

[0071] Another aspect of the present disclosure provides a method for the prevention or treatment of clinical conditions for which a monobactam is indicated, which method comprises administering to a patient in need of such prevention or treatment a prophylactically or therapeutically effective amount of a crystalline form or a crystalline hydrate form of the compound of formula I, in particular the crystalline hydrate form A of the compound of formula I, the crystalline hydrate form B of the compound of formula I, or the cry stal 1 i ne hydrate form D of the compound of formula I, or a mixture thereof. Such clinical conditions include bacterial infections, in particular gram-negative bacterial infections.

[0072] As used herein, the term “bacterial infection’7refers to the disease caused by bacteria, in particular gram-negative bacteria. Subjects infected with bacteria who have developed symptoms are considered to have a bacterial infection.

[0073] The present disclosure also provides the use of the crystalline forms of the compound of formula I, in particular the crystalline hydrate forms A, B and D of the compound of formula I, for the manufacture of a medicament for the prevention or treatment of clinical conditions for which a monobactam is indicated.

[0074] The present disclosure also provides pharmaceutical compositions comprising a crystalline form or crystalline hydrate form of the compound of formula I, in particular the crystalline hydrate forms A, B and D of the compound of formula I, or a mixture thereof, in association with one or more pharmaceutically acceptable carriers or excipients.

[0075] In one embodiment the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form or crystalline hydrate form of the compound of formula I in admixture with pharmaceutically acceptable excipients wherein the crystalline form of the compound of formula I comprises a detectable amount of the crystalline hydrate form A, B and / or D of the compound of formula I, or a mixture thereof, of the present disclosure.

[0076] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form or crystalline hydrate form of the compound of formula I in admixture with pharmaceutically acceptable excipients wherein cry stalline form of the compound of formula I comprises about 5% to about 100% by weight of the crystalline hydrate form A, B and / or D of the compound of formula I of the present disclosure, or a mixture thereof.

[0077] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form or crystalline hydrate form of the compound of formula I in admixture with pharmaceutically acceptable excipients wherein crystalline form of the compound of formula I comprises about 10% to about 100% by weight of the crystalline hydrate form A, B and / or D of the compound of formula I, or a mixture thereof, of the present disclosure.

[0078] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form or crystalline hydrate form of the compound of formula I in admixture with pharmaceutically acceptable excipients wherein crystalline of the compound of formula I comprises about 25% to about 100% by weight of the crystalline hydrate form A, B and / or D of the compound of formula I, or a mixture thereof, of the present disclosure.

[0079] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form or crystalline hydrate form of the compound of formula I in admixture with pharmaceutically acceptable excipients wherein crystalline form of the compound of formula I comprises about 50% to about 100% by weight of the crystalline hydrate form A, B and / or D of the compound of formula I, or a mixture thereof, of the present disclosure.

[0080] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form or crystalline hydrate form of the compound of formula I in admixture with pharmaceutically acceptable excipients wherein crystalline form of the compound of formula I comprises about 75% to about 100% by weight of the crystalline hydrate form A, B and / or D of the compound of formula I, or a mixture thereof, of the present disclosure.

[0081] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the cry stalline form of the compound of formula I in admixture with pharmaceutically acceptable excipients wherein crystalline form or crystalline hydrate form of the compound of formula I is substantially all crystalline hydrate form A, B and / or D of thecompound of formula 1 of the present disclosure (i.e., the compound of formula 1 is substantially phase pure crystalline hydrate form A, B and / or D of the compound of formula I).

[0082] The compositions in accordance with this disclosure are suitably in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories. The compositions are intended for oral, parenteral, intranasal, sublingual, or rectal administration, or for administration by injection, inhalation or insufflation. Formulation of the compositions according to this disclosure can conveniently be affected by methods known from the art, for example, as described in Remington's Pharmaceutical Sciences. 17thed., 1995.

[0083] The dosage regimen is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; and the renal and hepatic function of the patient. An ordinarily skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent or treat the progress of the condition.

[0084] Dosages of the present disclosure, when used for the indicated effects, will range between about 0.01 mg per kg of body (mg / kg / day) of the active moiety of the crystalline hydrate form of the compound of formula I to about 100 mg / kg / day of the active moiety of the crystalline hydrate form of the compound of formula I. In another embodiment, the dose range of active moiety of the crystalline hydrate form of the compound of formula I, administered to the patient is about 0.01 mg / kg to about 10 mg / kg of the patient’s body weight per dose. In another embodiment, the dose range of active moiety of the crystalline hydrate form of the compound of formula I, administered to the patient is about 0.1 mg / kg to about 3.4 mg / kg of the patient's body¬ weight per dose. The “active moiety of the crystalline hydrate form of the compound of formula I” is the compound of formula I.

[0085] For intravenous administration, the compositions are preferably provided in the form of intravenous solution containing 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg. 140 mg, 150 mg. 160 mg, 170 mg. 180 mg, 190 mg, 200 mg, 230 mg, 250 mg, 270 mg, 280 mg, 300 mg 330 mg, 350 mg, 360 mg, 390 mg, 420 mg, 450 mg, 480 mg, 500 mg, 510 mg, 540 mg, 550 mg, 570 mg, 600 mg, 630 mg, 650 mg, 680 mg, 700 mg, 720 mg, 750 mg, 780 mg, 800 mg, 810 mg, 830 mg, 850 mg, 860 mg, 890 mg, 900 mg, 930 mg, 950 mg, 960 mg, 980 mg. 990 mg, and 1000 mg of the active moiety of the crystalline hydrate form of the compound of formula I.

[0086] The crystalline forms of the present disclosure may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

[0087] In another embodiment, the dose of the active moiety of the crystalline hydrate form of the compound of formula I is 1 - 1000 mg / day. In a class of this embodiment, one fourth of the dose is given four times a day. In another class of this embodiment, one third of the dose is given three times a day. In another class of this embodiment, one half of the dose is given twice a day. In another class of this embodiment, the dose is given once a day.

[0088] In another embodiment, the dose of the active moiety of the crystalline hydrate form of the compound of formula I is 1 - 850 mg / day. In a class of this embodiment, one fourth of the dose is given four times a day. In another class of this embodiment, one third of the dose is given three times a day. In another class of this embodiment, one half of the dose is given twice a day. In another class of this embodiment, the dose is given once a day.

[0089] In the methods of the present disclosure, the crystalline forms of the compound of formula I can form the drug substance and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier' materials) suitably selected with respect to the intended form of administration. The cry stalline forms of the compound of formula I may be administered to a subject, or patient, in need thereof by any suitable means. Non-limiting examples of suitable methods of administration include, among others, administration as a liquid or solution via infusion, including IV infusion, and subcutaneous injection, parenteral, intravenous, or other forms of injection, including intramuscular; and oral administration as tablets, capsules, elixirs, syrups and the like.

[0090] For instance, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, magnesium stearate, calcium sulfate, mannitol, and the like; for oral administration in liquid form, the active pharmaceutical ingredient can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

[0091] According to a further aspect, the present disclosure provides a process for the preparation of the crystalline hydrate form A of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (compound of formula I).

[0092] In one embodiment, cry stalline hydrate form A of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I with a solvent;b) stirring the mixture;c) centrifuging to provide a wet solid; andd) drying the wet solid to a low relative humidity' to give a solid.

[0093] In a class of this embodiment, the solvent is pH 4 acetate buffer. In another class of this embodiment, the mixture is stirred at a temperature of about 26 °C. In another class of this embodiment, the solid is dried to a relative humidity between about 0 % to about 33 %. In another class of this embodiment, the solid is crystalline.

[0094] In another embodiment, crystalline hydrate form A of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I with pH 4 acetate buffer;b) stirring at 26 °C for 24 h;c) centrifuging to provide a wet slurry; andd) isolating the wet slurry.

[0095] In another embodiment, crystalline hydrate form A of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I with 50 mM pH 4 acetate buffer;b) stirring at 26 °C for 24 h;c) centrifuging to provide a wet solid; andd) drying the wet solid to a relative humidity between about 0 % and about 33 % to give a solid.

[0096] According to a further aspect, the present disclosure provides a process for the preparation of the crystalline hydrate form B of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (compound of formula I).

[0097] In one embodiment, crystalline hydrate form B of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I with solvent;b) stirring the mixture;c) centrifuging to provide a wet slurry; andd) freeze drying the slurry to give a solid.

[0098] In a class of this embodiment, the solvent is pH 4 acetate buffer. In another class of this embodiment, the mixture is stirred at a temperature of about 26 °C. In another class of this embodiment, the slurry' is freeze dried to a relative humidity' greater than about 33% to less than about 41%. In another class of this embodiment, the solid is crystalline.

[0099] In another embodiment, crystalline hydrate form B of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I with 50 mM pH 4 acetate buffer;b) stirring at 26 °C for 24 h;c) centrifuging to provide a solid;d) isolating the solid;e) washing the solid with cold deionized water; andf) drying the solid under ambient conditions.

[0100] In another embodiment, crystalline hydrate form B of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I with 50 mM pH 4 acetate buffer;b) stirring at 26 °C for 24 h;c) centrifuging to provide a wet slurry;d) freeze dry ing the slurry to give a solid.

[0101] In another embodiment, crystalline hydrate form B of the compound of formula I is prepared by a process comprising the steps of:a) stirring the compound of formula I in ethyl acetate and isopropanol to form a slurry; and b) freeze drying the slurry' to give a solid.

[0102] According to a further aspect, the present disclosure provides a process for the preparation of the crystalline hydrate form D of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)-chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (compound of formula I).

[0103] In one embodiment, cry stalline hydrate form D of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I cry stalline hydrate form A and form B with acetate buffer;b) stirring the mixture;c) centrifuging to provide a wet slurry; andd) drying the wet slurry to provide a solid.

[0104] In a class of this embodiment, the acetate buffer is pH 4 acetate buffer. In another class of this embodiment, the mixture is stirred at a temperature of about 26 °C. In another class of this embodiment, the wet solid is dried to a relative humidity' of about 55% or above. In another class of this embodiment, the solid is crystalline.

[0105] In one embodiment, crystalline hydrate form D of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I cry stalline hydrate form A with acetate buffer; b) stirring the mixture;c) centrifuging to provide a wet slurry; andd) drying the wet slurry to provide a solid.

[0106] In a class of this embodiment, the acetate buffer is pH 4 acetate buffer. In another class of this embodiment, the mixture is stirred at a temperature of about 26 °C. In another class of this embodiment, the wet solid is dried to a relative humidity of about 55% or greater than about 55%. In another class of this embodiment, the solid is crystalline.

[0107] In one embodiment, crystalline hydrate form D of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I cry stalline hydrate form B with acetate buffer; b) stirring the mixture;c) centrifuging to provide a wet slurry7; andd) drying the wet slurry to provide a solid.

[0108] In a class of this embodiment, the acetate buffer is pH 4 acetate buffer. In another class of this embodiment, the mixture is stirred at a temperature of about 26 °C. In another class of this embodiment, the wet solid is dried to a relative humidity of about 55% or above. In another class of this embodiment, the solid is crystalline.

[0109] In another embodiment, crystalline hydrate form D of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I cry stalline hydrate form A and crystalline hydrate form B with pH 4 acetate buffer;b) stirring at 26 °C for 24 h;c) centrifuging to provide a wet slurry; andd) isolating the wet solid; ande) drying under ambient conditions.

[0110] In another embodiment, crystalline hydrate form D of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I cry stalline hydrate form A with pH 4 acetate buffer; b) stirring at 26 °C for 24 h;c) centrifuging to provide a wet slurry7; andd) isolating the wet solid; ande) drying under ambient conditions.[OHl] In another embodiment, crystalline hydrate form D of the compound of formula I is prepared by a process comprising the steps of:a) treating the compound of formula I cry stalline hydrate form B with pH 4 acetate buffer; b) stirring at 26 °C for 24 h;c) centrifuging to provide a wet slurry; andd) isolating the wet solid; ande) drying under ambient conditions.

[0112] In another embodiment, crystalline hydrate form D of the compound of formula 1 is prepared by a process comprising the steps of:a) treating the compound of formula I with pH 4 acetate buffer;b) stirring at 26 °C for 24 h;c) filtering the mixture to give a solid;d) washing the solid with deionized water;e) treating the solid with pH 4 acetate bufferf) adding crystalline hydrate form D crystal seeds;g) stirring at 26 °C for 48 h;h) filtering the mixture to give a solid;i) washing the solid with de-ionized water; andj) drying the solid.

[0113] In a still further aspect, the present disclosure provides a method for the treatment and / or prevention of clinical conditions for which a monobactam is indicated, which method comprises administering to a patient in need of such prevention or treatment a prophylactically or therapeutically effective amount of the crystalline hydrate form A, form B and / or form D of the compound of formula I as defined above.DEFINITIONS

[0114] Certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure relates. That is, terms used herein have their ordinary meaning, which is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates.

[0115] As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the.” include their corresponding plural references unless the context clearly dictates otherwise.

[0116] Numerical values provided herein, and the use of the term “about’; may include variations of, for example, ± 0.1%, ± 0.2%, ± 0.3%, ± 0.4%, ± 0.5%, 0.75, ± 1%, ± 2%, ±3%, ± 4%, ± 5%, and ± 10% and their numerical equivalents. “About” when used to modify a numerically defined parameter (e.g., 20 values of an X-ray powder diffraction pattern measured using CuKa radiation, or the chemical shift of a13C or15N as described herein) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter; where appropriate, the stated parameter may be rounded to the nearest whole number. In addition, the term “or,” as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term “or” includes each listed alternative separately as well as their combination.

[0117] Compounds described herein may exist as tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of formula I.

[0118] The term “% enantiomeric excess” (abbreviated “ee”) shall mean the % major enantiomer less the % minor enantiomer. Thus, a 70% enantiomeric excess corresponds to formation of 85% of one enantiomer and 15% of the other. The term “enantiomeric excess” is synonymous with the term “optical purity.”

[0119] Exemplary' methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0120] The following non-limiting Examples are intended to illustrate this disclosure and should not be construed as being limitations on the scope or spirit of this disclosure.ABBREVIATIONS

[0121] A is angstrom, 0.1 nanometer; Ac is acetyl; Ambient is room temperature; aq. is aqueous; ACN is acetonitrile; AcOH is acetic acid; Aw or AW is active water; C2 iscry stallographic space group; CDChis deuterated chloroform; CV or cv is column volume(s); D is density (g / cm3); D2O is deuterium oxide; DCE is dichloroethane; DCM is dichloromethane; DEAD is diethyl azodicarboxylate; (DHQD)2AQN is 1.4-bis[(5-ethyl-l-azabicyclo[2.2.2]octan-2-yl)-(6-methoxyquinolin-4-yl)methoxy]anthracene-9, 10-dione; DIEA or DIPEA is diisopropylethylamine; DMA is dimethylacetamide; DMAP is 4-dimethyl-aminopyridine, also known as N,N-dimethylamino-pyridine; DME is dimethoxyethane; DMF is N,N-dimethyl-formamide; DMSO is dimethyl sulfoxide; eq. or equiv. is equivalent(s); Et is ethyl; Et?N istriethyl amine; Et20 is diethyl ether; EA or EtOAc is ethyl acetate; EtOH is ethanol; equiv is equivalents; FA is formic acid; F is structure Factor: g is gram(s); h or hr or hrs is hour(s); hex is hexane; HPLC is high-performance liquid chromatography; Int is intermediate; IPA is isopropyl alcohol; L or 1 is liter(s); LC / MS or LC-MS is liquid chromatography / mass spectrometry; M is molar; mM is millimolar; mmol is millimoles: min is minute(s); mg is milligram(s); ml, mL or ML is milliliter(s); Me is methyl: MeCN is acetonitrile; MeO is methoxy: MeOH is methanol; MPLC is medium pressure liquid chromatography; MTBE is methyl tert-butyl ether; N is normal; NaBH(OAc)3 is sodium triacetoxyborohydride; NBS is N-bromo-succinimide; NCS is N-chlorosuccinimide; NEts is trietheyl amine: NMR is nuclear magnetic resonance; MS is mass spectrometry; MTBE is methyl tert-butyl ether; MW is molecular weight; Pd / C is palladium on carbon; Pd(AcO)2 is palladium (II) acetate; PE is petroleum ether; PG is protective group; Ph is phenyl; Ph?P is triphenyl phosphine; R is R-factor or R -factor determined from F2; RP is reverse phase; RP-HPLCis reverse-phase high-performance liquid chromatography; rpm is revolutions per minute; ft, r.t., R.T. or RT is room temperature; S is goodness-of-fit on F2; sat’d is saturated: SFC is super critical fluid chromatography; tBu is tert-butyl; tBuOH is tert-butyl alcohol: TBAF is tetrabutylammonium fluoride; t-BuOH is tert-butyl alcohol; TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin layer chromatography; TMS is trimethylsilyl; TMS-C1 is trimethylsilyl chloride; V or v is volume; wt % or wt.% is weight percentage; Z is formula units in unit cell; Z is number of molecules in the asymmetric unit; and o is standard deviation.INTERMEDIATE 1Preparation of Intermediate 1cIntermediate 1a Intermediate 1b Intermediate 1c

[0122] Step A- Synthesis of Intermediate- la: To a solution of tert-buty l 2-(diethoxyphosphoryl)-propanoate (2150.0 g, 8.06 mol, 0.95 eq) in THF (8400 mL) stirred at ambient temperature, was added NaH (339.3 g, 8.48 mol, 60% purity, 1.0 eq) in several portions. The mixture was stirred at 30-40°C for 3 h. Then a solution of 3-(2-bromo-5-chlorophenyl)propanal (2100.0 g, 8.48 mol, 1.0 eq) in THF (4200 mL) was added dropwise to the above mixture at 30-50°C. After the addition, the mixture was stirred at 20-40°C for 1 h, thenpoured into ice water (10 L), and diluted with EtOAc (10 L). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 L). The combined organic layers were washed with brine (10 L), and concentrated under reduced pressure. The resulting residue w as purified by column chromatography on silica gel eluting with petroleum ether: ethyl acetate (1:0 -10: 1) to give intermediate la. 'H-NMR (400 MHz. CDCh): 57.47 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 7.07 (dd, J = 8.5, 2.6 Hz, 1H), 6.71 (td, J = 7.5, 1.5 Hz, 1H), 2.93 - 2.71 (m, 2H), 2.63 - 2.37 (m, 2H), 1.78 (d, J = 1.3 Hz, 3H), 1.52 (s, 9H).

[0123] Step B- Synthesis of Intermediate lb: Into a 50 L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, were added K2CO3 (2188 g, 15.84 mol), potassium ferricyanide (5218 g, 15.84 mol), tetraoxodipotassium osmium (38.1 g, 0.105 mol), (DHQD)2AQN (90.1 g, 0.105 mol) and a solution of intermediate la (1900 g, 5.28 mol) in tertbutanol / water (19 L / 19 L). The resulting mixture was stirred at room temperature for 2 days. Then the reaction mixture was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate. The resulting solids were filtered out. The filtrate was concentrated under vacuum, and the resulting residue w as purified by a silica gel column eluting with ethyl acetate / petroleum ether (1 / 100-1 / 10) to give intermediate lb. LC-MS: m / z 417.0 [M+Na]+.

[0124] Step C- Synthesis of Intermediate 1c: Into a 20-L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, were placed CS2CO3 (2317.2 g, 7112.01 mmol) and Pd(AcO)2 (39.9 g, 177.80 mmol) in toluene (14 L). Then 2-(di-tert-butylphosphino)biphenyl (106.1 g, 355.60 mmol) was slowly added over 30 min. To this mixture was added intermediate lb (1400 g, 3556.01 mmol). The reaction mixture was stirred for 20 h at 90 °C, then cooled to room temperature with a water / ice bath. The resulting solids were filtered off, and the filtrate w as concentrated under reduced pressure. The resulting residue was purified on a silica gel column eluting with ethyl acetate / petroleum ether (1 / 100-1 / 5) to give intermediate 1c. 'H-NMR (400 MHz, CDCh): 57.07-7.00 (m, 2H), 6.67 (d, J = 8.3 Hz, 1H), 4.14 (dd, J = 11.0, 2.4 Hz. 1H), 3.03 - 2.60 (m, 2H), 2.23 - 1.86 (m, 2H), 1.53 (s, 9H). 1.41 (s, 3H).INTERMEDIATE 2Preparation of Intermediate 2bONHBocIntermediate 2a Intermediate 2b

[0125] Step A- Synthesis of Intermediate 2a: Into a 2-L 4-necked round-bottom flask was placed a solution of intermediate 1c (460 g, 1.47 mol) in toluene (4800 mL), followed by the addition of sodium hydride (60 wt %, 70.8 g, 1.77 mol) in several batches at 27 °C. The mixture was stirred at 27°C for 1 h. Then a solution of amino 2,4,6-trimethylbenzene-l -sulfonate (380.4 g, 1.77 mol) in DCM (1200 mL) was added dropwise with stirring at 27 °C. The reaction mixture was stirred at 27 °C for 2 h. The reaction w as then quenched by the addition of water (2000 mL) and extracted with MTBE (2 x 2 L). The organic layers were combined, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified on a silica gel column eluting with EtOAc / PE (1: 10) to give intermediate 2a. 'H-NMR (400 MHz, CDCh): 57.08-6.96 (m, 2H), 6.96 (overlap, 1H), 6.77 (d, J = 9.4 Hz, 1H), 4.20 (dd, J = 11.4, 1.9 Hz, 1H), 2.99 - 2.62 (m, 2H), 2.06 (ddt, J = 13.6, 5.9, 2.1 Hz, 1H), 1.87 (dtd, J = 13.6, 12.0, 5.8 Hz, 1H), 1.54 (s, 9H), 1.53 (s, 3H).

[0126] Step B- Synthesis of Intermediate 2b: Into a 5 L 4-necked round-bottom flask was placed intermediate 2a (500 g, 1525.27 mmol) and di-tert-butyl dicarbonate (399.00 g, 1828.18 mmol) in ethyl alcohol (5 L). The reaction w as stirred for 5 h at 50 °C, then concentrated under vacuum. The resulting crude product was purified by slurrying with hexanes. The solids were collected by filtration to afford intermediate 2b. 'H NMR (400MHz, CDCh): 57.53 (s. 1H), 6.99 (t, 2H), 6.68 (t, 1H), 4.21 (q, 1H), 2.82 (t, 2H), 2.17-2.12 (m, 2H), 1.55-1.45 (m, 21H).INTERMEDIATE 3Preparation of Intermediate 3c

[0127] Step A- Synthesis of Intermediate 3a: To a mixture of intermediate 2b (8.0 g, 18.69 mmol), potassium hexacyanoferrate(II) trihydrate (3.95 g, 9.35 mmol), sodium carbonate (0.248 g, 2.337 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-amino-l,l'-biphenyl-2-yl) palladium(II) (1.471 g, 1.869 mmol) were added ACN (64 mL) and water (60 mL), both of which had been sparged with nitrogen for 1 h. The reaction vessel was evacuated and filled with nitrogen before sealing. Then the reaction was heated at 80 °C and stirred for 2 h. The reaction was then partitioned between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered through a Celite™ pad. The resulting filtrate was concentrated in vacuo to give a crude residue, which was purified via silica gel chromatography (ISCO 220 g; 0-70% EtOAc / hexanes to give the desired compound. LC-MS: m / z 419.2 [M+H]+.

[0128] Step B- Synthesis of Intermediate 3b: To a mixture of intermediate 3a (4.81 g, 11.49 mmol), MgCL (1.641 g, 17.24 mmol), and NaSH (1.933 g, 34.5 mmol) was added nitrogen-sparged anhydrous DMF (20.5 mL) under an atmosphere of nitrogen. The reaction mixture was evacuated and filled with nitrogen before capping and stirring at ambient temperature for 21 h. Then the reaction was cooled to 0°C and quenched with saturated aqueous NH4CI and water. The resulting mixture was extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a crude residue, which was purified via silica gel chromatography (ISCO, 220 g; 0-100% EtOAc / hexanes) to give the desired compound. LC-MS: m / z 453.2 [M+H]+.

[0129] Step C- Synthesis of Intermediate 3c: To a solution of intermediate 3b (4.85 g, 10.72 mmol) in anhydrous ether (35 mL) was added iodomethane (0.804 mL, 12.86 mmol) at ambient temperature. The reaction was sealed and stirred for 24 h. Then the ether supernatant was decanted off. The insoluble sticky oil was triturated with ether (15 mL). The resulting oil was dried under high vacuum to give intermediate 3c. The decanted ether layers were also combined and concentrated in vacuo. To the resulting residue was added 1:1 hexanes / ether (30 mL), and the resulting solid material was collected by filtration, washed with 1:1 hexanes / Et2O (20 mL) and dried under vacuum to give an additional amount of intermediate 3c. The combined crude product was used in subsequent reactions without further purification. LC-MS: m / z 468.2 [M+H]+.INTERMEDIATE 4Preparation of Intermediate 4Intermediate 4

[0130] Intermediate 4 was prepared using the method described in Patent Publication No: WO 2017 / 106064.INTERMEDIATE 5Preparation of Intermediate 5Intermediate 5

[0131] A flask (250 rnL) was charged with Intermediate 4 (10 g, 21.5 mmol) and CH2CI2 (43 mL), and the solution was cooled to 0 °C. Then TFA (86 mL, 1116 mmol) was added via syringe. The reaction mixture was stirred at 0 °C for 5 h, then concentrated under vacuum without heating to give a residue (—20 mL total volume). DCM (100 mL) was added to the residue and the mixture was concentrated under vacuum without heating to ~20 mL total volume. This process was repeated four times to drive out most of the TFA. Finally, the solvent wasremoved completely under vacuum. To the resulting residue was added water (100 mL). After stirred for 30 min, the mixture was filtered, and the filter cake was rinsed with water (1 volume of cake) and then collected. The filter cake was dissolved in 1:1 acetonitrile / water (50 mL) and the mixture was lyophilized overnight to provide intermediate 5. LC-MS: m / z 365.3 [M+H]+.JH NMR (500 MHz, DMSO-de) 5: 9.67 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.57 (s, 2H). 4.59 (d, J = 7.9 Hz, 1H), 1.44 (s, 3H), 1.25 (s, 3H).EXAMPLE 1Synthesis of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)carbamimidoyl)chroman-2-yl)-2- ((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l -(sulfooxy )azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid (the compound of formula I)Intermediate 8bIntermediate 5

[0132] Step A- Synthesis of Intermediate 8a: To a vial containing a mixture of cis-tert-butyl N-(3-aminocyclobutyl)carbamate (0.065 mL, 0.385 mmol) in anhydrous acetonitrile (1 mL) were added a solution of intermediate 3c (0.11 g, 0.238 mmol) and acetic acid (0.044 mL, 0.771 mmol) in anhydrous acetonitrile (1 mL). The reaction mixture was heated at 65 °C for 2 h, then cooled to ambient temperature and purified via reverse phase HPLC (ISCO C18Aq 50 g product elutes at 65% ACN + 0.05% TFA / water + 0.05% TFA) with gradient elution 0-100% ACN + 0.05% TFA / water + 0.05% TFA. The desired fractions were collected and concentrated in vacuo. The resulting aqueous residue was partitioned between brine and ethyl acetate. The brine was back extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo to give the intermediate 8a. LC-MS: m / z 605.4[M+H]+.

[0133] Step B- Synthesis of Intermediate 8b: To a vial containing intermediate 8a (0.1108 g, 0.183 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (2 mL) at ambient temperature. The reaction mixture was stirred for 16.5 h, then a solution of 4: 1 MeOH / toluene (10 mL) was added to the reaction and the mixture was concentrated in vacuo. The resulting residue was azeotroped with 4: 1 MeOH / toluene (10 mL) and dried under high vacuum to give the intermediate 8b. LC-MS: m / z 349.16 [M+H]+.Step C- Synthesis of the formic acid salt of the Compound of formula I: To a vial charged with intermediate 8b (0.183 mmol), intermediate 5 (79 wt%, 0.129 g, 0.199 mmol), and powdered molecular sieves 4A (325 mesh particle; 0.100 g, dried under high vacuum with heat) was added anhydrous dimethylacetamide (1.2 mL) at ambient temperature. The reaction mixture was stirred for 18 h, then filtered through a Celite™ pad. The Celite™ pad was washed well with MeOH. The filtrate was concentrated in vacuo, and the remaining residue w as cooled to 0 °C, followed by the addition of DCM (6 mL) with stirring. The resulting precipitate was collected by centrifugation (4000 rpm). The supernatant was decanted and the insoluble solid was triturated with DCM (3 mL). The centrifugation and supernatant decanting steps were repeated to give a crude solid, which was purified by RP HPLC (XSelect CSH Prep Cl 8; 5 pM OBD; 50 X 250mm; 0%-l 3% ACN / (water + 0.16% TFA) over 11 min.; isocratic at 13% ACN / (water + 0.16% TFA) for 14 min). The product fractions were collected, concentrated in vacuo to remove acetonitrile, and the aqueous layer was directly loaded onto an Amberchrom CG161M column (26 g), w ashed with 9 CV of (water + 0.1% FA), and eluted off with 3 CV of 100% (ACN + 0.1% FA) followed by 3 CV of 50% (ACN + 0.1% FA) / (w ater + 0.1% FA). The desired fractions were collected, concentrated in vacuo, and the resulting aqueous residue was lyophilized to give the title compound as the formic acid salt (the formic acid salt of the compound of formula I). LC-MS: m / z 695.2 [M+H]+.1HNMR (400 MHz, 4: 1 D2O / d-DMSO) 8: 7.36 (s, 1H), 7.35-7.29 (m, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.81 (s, 1H), 4.57 (s, 1H), 4.32 (d, J = 11.6 Hz, 1H), 3.96 (t, J = 8.0 Hz, 1H), 3.62-3.51 (m, 1H), 2.85 (dt, J = 7.5, 2.6 Hz, 2H), 2.72 (m, 2H), 2.27 (q. J = 8.9 Hz. 2H), 2.01 (d, J = 12.2 Hz, 1H). 1.65 (m 1H). 1.45 (s, 3H). 1.36 (s. 3H), 1.18 (s, 3H).

[0134] The intermediates, compound of formula I, the trifluoroacetic acid salt of the compound of formula I, and the formic acid salt of the compound of formula I may be synthesized according to the procedure disclosed in WO 2023 / 091438.EXAMPLE 2Preparation of crystalline hydrate form A of (S)-2-((R)-6-(N-((ls,3S)-3- aminocyclobutyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2- dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (Compound of Formula I, cry stalline hydrate form A)

[0135] Synthesis of Crystalline Hydrate Form A (or Type A) To (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)-amino)oxy)propanoic acid (21.4 mg, 0.031 mmol) was added 50 mM pH 4 sodium acetate buffer (0.24 mL). The mixture was stirred at 26 °C for 24 h. Then the mixture was centrifuged at 15.000 rpm for 5 minutes. The sample was isolated to provide a wet slurry for characterization with X-ray diffraction (XRD). The crystal form of the slurry solids was shown to be crystalline hydrate form (or type) A of the compound of formula I by X-ray powder diffraction.

[0136] X-ray powder diffraction studies are widely used to characterize molecular structures, crystallinity, and polymorphism. The X-ray powder diffraction was done using an X Pert Pro instrument (PANalytical B. V., Almelo, The Netherlands). Samples were prepared on Si zeroreturn wafers. A typical scan is from 20 of 2 to 40 °, with an Empyrean Cu-LFF source of wavelength (1.5406A) operating at 45 kV and 40 mA.

[0137] Crystalline hydrate form A of the Compound of formula I is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 10.99, about 11.89, about 14.65, about 15.6, about 16.85, about 20.68, and about 22.19 °20.FWHM LeftPos. [°20] Height [cts] d-spacing [A] Rel. Int. [%][°20]10.99 55.29 0.39 8.05 5.5311.89 91.72 0.63 7.43 9.1814.65 999.06 0.16 6.04 100.0015.65 192.72 0.24 5.66 19.2916.85 125.87 0.24 5.26 12.6020.68 166.01 0.39 4.29 16.6222.19 296.49 0.31 4.00 29.68

[0138] FIG. 1 shows the X-ray diffraction pattern (XRDP) for the crystalline hydrate form A of the compound of formula I. The crystalline hydrate form A of the compound of formula Iexhibited characteristic diffraction peaks corresponding to d-spacings of about 14.65, about 15.65, and about 22.19 angstroms. The crystalline hydrate form A of the compound of formula I was further characterized by the d-spacings of about 11.89, about 16.85, and about 20.68 angstroms. The crystalline hydrate form A of the compound of formula I was even further characterized by the d-spacing of 10.99 angstroms.

[0139] In addition to the X-ray powder diffraction patterns described above, the crystalline hydrate form D of the compound of formula I was further characterized by its TGA and DSC spectra.

[0140] FIG. 2 shows the thermogravimetric analysis (TGA) curve for the crystalline hydrate form A of compound of formula I.

[0141] FIG. 2 also shows the differential scanning calorimetry (DSC) curve for the cry stal I i ne hydrate form A of the compound of structural formula I.

[0142] Crystalline hydrate form A of the compound of formula I may also be obtained by drying of a slu ' of the compound of formula I from water to a relative humidity between 0-33 % RH.EXAMPLE 3Preparation of crystalline hydrate form B of (S)-2-((R)-6-(N-((ls,3S)-3- aminocyclobutyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2- dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (Compound of Formula I, crystalline hydrate form B)

[0143] Synthesis of Crystalline Hydrate Form B (or Type B) To (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo- 1 -(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (100 mg, 0.144 mmol) was added 50 mM pH 4 sodium acetate buffer (1 mL). The mixture was stirred at 26 °C for 24 h. Then the mixture was centrifuged at 15,000 rpm for 5 minutes. The resulting solid sample was isolated, washed with ice-cold deionized water twice, and dried under ambient conditions. The resulting solid was characterized by X-ray diffraction (XRD). The crystal form of the resulting solid was shown to be crystalline hydrate form B of the compound of formula I by X-ray powder diffraction.

[0144] X-ray powder diffraction studies are widely used to characterize molecular structures, crystallinity, and polymorphism. The X-ray powder diffraction was done using an X’Pert Proinstrument (PANalytical B. V., Almelo, The Netherlands). Samples were prepared on Si zeroreturn wafers. A typical scan is from 20 of 2 to 40 °, with an Empyrean Cu-LFF source of wavelength (1.5406A) operating at 45 kV and 40 mA.

[0145] The crystalline hydrate form B of the compound of formula I is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 9.96, about 12.08, about 14.82, about 15.77, about 17.10, about 18.47, about 20.79, about 22.29, about 23.69, about 26.63, and about 32.81 °20.Pos. [°20] Height [cts] d-spacing [A] Rel. Int. [%]9.96 155.52 8.87 6.1712.08 662.07 7.32 26.2614.82 2521.56 5.97 100.0015.77 1015.47 5.61 40.2717.10 822.93 5.18 32.6418.47 823.39 4.80 32.6520.79 1669.66 4.27 66.2222.29 2065.31 3.99 81.9123.69 763.16 3.75 30.2726.63 245.21 3.35 9.7232.81 70.21 2.73 2.78

[0146] FIG. 3 shows the X-ray diffraction pattern (XRDP) for the crystalline hydrate form B of the compound of formula I. The crystalline hydrate form B of the compound of formula I exhibited characteristic diffraction peaks corresponding to d-spacings of about 14.82, about 15.77, and about 17.10 angstroms. The crystalline hydrate form B of the compound of formula I was further characterized by the d-spacings of about 18.47, about 20.79, and about 22.29 angstroms. The crystalline hyrate form B of the compound of formula I was even further characterized by the d-spacings of about 12.08, and about 23.69 angstroms.

[0147] In addition to the X-ray powder diffraction patterns described above, the cry stal I ine hydrate form B of the compound of formula I was further characterized by its TGA and DSC spectra.

[0148] FIG. 4 shows the thermogravimetric analysis (TGA) curve for the crystalline hydrate form B of compound of formula I. Thermogravimetric analysis was carried out on a TA Q 500 Thermogravimetric Analyzer (TA Instrument). Samples (5-20 mg) in open pans were heated from RT to 300°C at 10°C / min, with a nitrogen purge of 55 rnL / min.TG of the crystalline hydrate form B (type B) of the compound of formula I Event # Solvent ID by FT-IR Weight Loss (%) End Temperature (°C)1 water 10.2 145

[0149] FIG. 5 shows the differential scanning calorimetry (DSC) curve for the crystalline hydrate form B of the compound of structural formula I. A TA Instruments Discovery7Differential Scanning Calorimeter was used to monitor the thermal events as a function of temperature increase. Samples (2-5 mg) in aluminum hermetic pans with pin holes were heated from 10 to 300°C at a heating rate of 10°C / min.

[0150] Cry stalline hy drate form B of the compound of formula I may also be obtained from a wet slurry7of the compound of formula I in ethyl acetate and isopropanol. Additionally, crystalline hydrate form B of the compound of formula I may also be obtained from drying a slurry7of the compound of formula I in ethyl acetate and isopropanol.EXAMPLE 4Preparation of crystalline hydrate form D of (S)-2-((R)-6-(N-((ls,3S)-3- aminocyclobutyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2- dimethyl-4-oxo- 1 -(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (Compound of Formula I, crystalline hydrate form D)

[0151] Synthesis of Crystalline Hydrate Form D (or Type D) A slurry' suspension of (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l -(sulfooxy)azeti din-3 -yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid crystalline hydrate form A (approximately 15 mg) and (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyl)-carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l -(sulfooxy )azeti din-3 -yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid cry stalline hydrate form B (approximately 15 mg each) in 50 mM pH 4 sodium acetate buffer was prepared at a target concentration of 10 mg / mL. The slurry7was mixed thoroughly and stirred at room temperature for 24 hours. The slurry was then transferred into a centrifuge tube and centrifuged at 15,000 rpm for 5 minutes. The wet solid was transferred to a vial and allowed to dry7completely under ambient conditions. The resulting solid was characterized by X-ray diffraction (XRD), which showed that the cry stalline material was crystalline hydrate form (or type) D of the compound of formula I.

[0152] Alternate Synthesis of Crystalline Hydrate Form D (or Type D) To (S)-2-((R)-6-(N-((ls,3S)-3-aminocyclobutyd)carbamimidoyl)chroman-2-yl)-2-((((Z)-l-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (1 g, 1.44 mmol) was added 50 mM pH 4 sodium acetate buffer (10 mL) to give a gummy mixture. The mixture was stirred at 26 °C for 3 h. Then the mixture w as fdtered and washed with de-ionized water (20 mL x 2) to give a solid. To the resulting white solid was added 50 mM pH 4 acetate buffer (7.2 mL) and type D crystal seeds (about 1 mg). Then the mixture was stirred at 26 °C for another 48 h. The mixture was then filtered and washed with de-ionized water (20 mL x 2) to give a solid. XRD showed the crystalline material was crystalline hydrate form (or type) D of the compound of formula I.

[0153] The crystal form of the solids was shown to be crystalline hydrate form D by X-ray powder diffraction and thermogravimetric analysis. X-ray powder diffraction studies are widely used to characterize molecular structures, crystallinity, and polymorphism. The X-ray powder diffraction was done using an X’Pert Pro instrument (PANalytical B. V., Almelo, The Netherlands). Samples were prepared on Si zero-return wafers. A typical scan is from 20 of 2 to 40 °, with an Empyrean Cu-LFF source of wavelength (1.5406A) operating at 45 kV and 40 mA.

[0154] The crystalline hydrate Form D of the compound of formula I is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 8.03, about 9.23, about 10.77, about 13.55, about 14.62, about 17.64, about 20.02, about 21.59, and about 26.65 °20.Pos. [°20] Height [cts] d-spacing [A] Rel. Int. [%]8.03 524.54 11.01 88.149.23 52.10 9.58 8.7510.77 595.15 8.21 100.0013.55 285.67 6.53 48.0014.62 578.49 6.05 97.2017.64 284.37 5.02 47.7820.02 425.94 4.43 71.5721.59 274.18 4.1 1 46.0726.65 112.04 3.34 18.82

[0155] FIG. 6 shows the X-ray diffraction pattern (XRDP) for the crystalline hydrate form D of the compound of formula I. The crystalline hydrate form D of the compound of formula I exhibited characteristic diffraction peaks corresponding to d-spacings of about 10.77, about14.62, and about 20.02 angstroms. The crystalline hydrate form D of the compound of formula 1 was further characterized by the d-spacings of about 8.03, about 13.55, and about 17.64 angstroms. The cry stalline hydrate form D of the compound of formula I was even further characterized by the d-spacings of about 21.59, and about 26.65 angstroms. The crystalline hydrate form D of the compound of formula I was even further characterized by the d-spacing of about 9.23 angstroms.

[0156] In addition to the X-ray powder diffraction patterns described above, the crystalline hydrate form D of the compound of formula I was further characterized by its TGA and DSC spectra.

[0157] FIG. 7 shows the thermogravimetric analysis (TGA) curve for the crystalline hydrate form D of compound of formula I. Thermogravimetric analysis was carried out on a TA Q 500 Thermogravimetric Analyzer (TA Instrument). Samples (5-20 mg) in open pans were heated from RT to 300°C at 10°C / min, with a nitrogen purge of 55 mL / min.TG of the cry stalline hydrate form D (ty pe D) o: 'the compound of formula IEvent # Solvent ID by FT-IR Weight Loss (%) End Temperature (°C) 1 Water 10.1 65 2 Water 14.9 1003 Water 16.4 145

[0158] FIG. 8 shows the differential scanning calorimetry (DSC) curve for the crystalline hydrate form D of the compound of structural formula I. A TA Instruments Discovery7Differential Scanning Calorimeter was used to monitor the thermal events as a function of temperature increase. Samples (2-5 mg) in aluminum hermetic pans with pin holes were heated from 10 to 300°C at a heating rate of 10°C / min.DSC of the crystalline hydrate form D (type D) of the compound of formula IDescription Type (exo / endo) (°C) (°C) AH (J / g) N / A Endo 44.9 57.4 43.1 N / A Endo 80.9 89.1 11.3EXAMPLE 5Preparation of Cry stalline Hydrate Forms A and D of the compound of formula I with Humidity

[0159] Preparation of Compound of formula I Form (or Type) A via Relative Humidity (RH) using Salt Chamber Conditions Six 20-rnL vials were each filled with 30 mg of the compound of formula I. Each vial was then placed in a salt chamber. Below is the description of the six salt chambers:Vial 1 was placed in a salt chamber with 11 % RH target condition. The target RH was achieved by placing saturated lithium chloride solution at the bottom of the chamber.Vial 2 was placed in a salt chamber with 23 % RH target condition. The target RH was achieved by placing saturated potassium acetate solution at the bottom of the chamber.Vial 3 was placed in a salt chamber with 33 % RH target condition. The target RH was achieved by placing saturated magnesium chloride solution at the bottom of the chamber.Vial 4 was placed in a salt chamber with 43 % RH target condition. The target RH was achieved by placing saturated potassium carbonate at the bottom of the chamber.Vial 5 was placed in a salt chamber with 55 % RH target condition. The target RH was achieved by placing saturated magnesium nitrate solution at the bottom of the chamber.Vial 6 was placed in a salt chamber with 75 % RH target condition. The target RH was achieved by placing saturated sodium chloride solution at the bottom of the chamber.

[0160] The six salt chambers containing the vials were placed in a cold room. After 4 days, XRPD of each sample was collected. The XRPD spectra taken for vials 1, 2, and 3 each showed XRPD patterns that complied with the crystalline hydrate Form A (or Type A) of the compound of formula I at 11% RH, 23% RH and 33% RH. The XRPD spectra taken for vials 4, 5, and 6 each showed XRPD patterns that complied with cry stalline hydrate Form D (or Type D) of the compound of formula I at 43% RH, 55% RH and 75% RH.EXAMPLE 6Stability and Interconversion of Crystalline Hydrate Forms B and D with Humidity

[0161] Approximately 40 mg of crystalline hydrate form (or type) D of the compound of formula I was dispensed into each of five 2 mL clear glass GC vials. Each vial was placed inside of a separate 50 mL Light House™ scintillation vial that contained potassium hydroxide solution (2.5 mL) at 5 different molalites. The five 50 mL Light House™ scintillation vials were each crimp sealed with rubber septum crimp caps. All five sealed vials were equilibrated at 25 °C for approximately 24 hours. Then the relative humidity (water activity) was determined in each LightHouse™ scintillation vial using the Light House™ FMS-1400 Headspace moisture Analyzer instrument. The 2 mL clear glass GC vials were removed from the sealed 50 mL Light House™ scintillation vials and the cry stalline solid in each vial was characterized by PXRD.

[0162] Based on the experimental conditions shown in Table 1, Crystalline Hydrate Form (or Type) D of the compound of formula I is the stable form (or phase) from 54% to 60% relative humidity (RH). As also shown in Table 1, Cry stalline Hydrate Form (or Type) B of the compound of formula I is the stable form (or phase) from 41% to 50% relative humidity (RH).Table 1Molality of Amount of Equilibration Analyzed Aw / % PXRDKOH solution Type D (mg) Temperature RH after results:equilibration Crystal Form9.0 43.4 25 °C 60.166 Type D(0.60Aw)10.0 43.1 25 °C 54.299 Type D(0.54Aw)11.0 42.4 25 °C 50.478 Mixture ofType B &(0.50 Aw)Type D12.0 42.3 25 °C 46.066 Mostly TypeB(0.46 Aw)13.0 45.7 25 °C 41.077 Type B(0.41Aw)

[0163] Figure 9 shows the phase boundaries correlating to: 1) crystalline hydrate form (or type) A of the compound of formula I with respect to relative humidity' (RH); 2) crystalline hydrate form (or type) B of the compound of formula I with respect to relative humidity (RH); and 3) crystalline hydrate form (or type) D of the compound of formula I with respect to relative humidity (RH). The crystalline hydrate form B of the compound of formula I exhibits stability under 45% relative humidity' (RH). The crystalline hydrate form D of the compound of formula I is most stable above 55% relative humidity' (RH).

[0164] It will be appreciated that various of the above-discussed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also, that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art that are also intended to be encompassed by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A cry stalline form of the compound of formula IIor a pharmaceutically acceptable salt or hydrate thereof.

2. A crystalline hydrate form of the compound of formula I of Claim 13. The crystalline form of the compound of formula I of Claim 1, wherein the crystalline form is crystalline hydrate form A.

4. The cry stalline hydrate form A of Claim 3 characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 14.65, 15.

65. and 22.19 angstroms.

5. The crystalline hydrate form A of Claim 4 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 11.89, 16.

85. and 20.68 angstroms.

6. The cry stalline hydrate form A of Claim 5 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 10.99 angstroms.

7. The crystalline hydrate form A of Claim 3 further characterized by the X-ray powder diffraction pattern of FIG. 1.

8. The cry stalline hydrate form A of Claim 3 characterized by the thermogravimetric analysis curve of FIG. 2.

9. The crystalline hydrate form A of Claim 3 characterized by the differential scanning calorimetric curve of FIG. 2.

10. The cry stalline form of the compound of Claim 1 comprising a detectable amount of the crystalline hydrate form A.

11. The crystalline form of the compound of formula I of Claim 1 comprising about 1 % to about 100% by weight of the crystalline hydrate form A.

12. The crystalline form of the compound of formula I of Claim 1, wherein the crystalline form is cry stalline hydrate form B.

13. The cry stalline hydrate form B of Claim 12 characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of: 14.82, 15.77, and 17.10 angstroms.

14. The crystalline hydrate form B of Claim 13 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of: 18.47, 20.

79. and 22.29 angstroms.

15. The cry stalline hydrate form B of Claim 14 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of: 12.08, and 23.69 angstroms.

16. The crystalline hydrate form B of Claim 12 further characterized by the X-ray powder diffraction pattern of FIG. 3.

17. The cry stalline hydrate form B of Claim 12 characterized by the thermogravimetric analysis curve of FIG. 4.

18. The crystalline hydrate form B of Claim 12 characterized by the differential scanning calorimetric curve of FIG. 5.

19. The cry stalline form of the compound of formula I of Claim 1 comprising a detectable amount of the crystalline hydrate form B.

20. The crystalline form of the compound of formula I of Claim 1 comprising about 1% to about 100% by weight of the crystalline hydrate form B.

21. The crystalline form of the compound of formula I of Claim 1, wherein the crystalline form is cry stalline hydrate form D.

22. The cry stalline hydrate form D of Claim 21 characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of: 10.77, 14.62, and 20.02 angstroms.

23. The crystalline hydrate form D of Claim 22 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of: 8.03, 13.55, and 17.64 angstroms.

24. The cry stalline hydrate form D of Claim 23 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of: 21.59, and 26.65 angstroms.

25. The crystalline hydrate form D of Claim 21 further characterized by the X-ray powder diffraction pattern of FIG. 6.

26. The cry stalline hydrate form D of Claim 21 characterized by the thermogravimetric analysis curve of FIG. 7.

27. The crystalline hydrate form D of Claim 21 characterized by the differential scanning calorimetric curve of FIG. 8.

28. The cry stalline form of the compound of formula I of Claim 1 comprising a detectable amount of the crystalline hydrate form D.

29. The crystalline form of the compound of formula I of Claim 1 comprising about 1% to about 100% by weight of the crystalline hydrate form D.

30. A pharmaceutical composition comprising a therapeutically effective amount of the cry stalline hydrate form of the compound of Claim 1 and one or more pharmaceutically acceptable carriers.

31. The pharmaceutical composition of Claim 30 wherein the pharmaceutical composition is a solid dosage form for oral administration.

32. The pharmaceutical composition of Claim 30 wherein the pharmaceutical composition is a sterile solution for i.v. infusion, parenteral, intravenous, or intramuscular administration.

33. A pharmaceutical composition according to Claim 30 further comprising a therapeutically effective amount of a beta-lactamase inhibitor compound is selected from: relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, zidebactam, enmetazobactam and durlobactam.

34. A method of treating a bacterial infection comprising administering to a patient in need of such treatment a therapeutically effective amount of the crystalline hydrate form of the compound of formula I of Claim 1, wherein the bacteria infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.

35. The method of Claim 32 further comprising administering to a subject in need of such treatment a therapeutically effective amount of a beta-lactamase inhibitor compound, wherein the beta-lactamase inhibitor compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, zidebactam, enmetazobactam and durlobactam.

36. Use of a crystalline hydrate form of the compound of Formula 1 of Claim 1 for treating a bacterial infection, or in the manufacture of a medicament for treating a bacterial infection, wherein the bacterial infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.

37. The use of Claim 34 further comprising administering the compound of Claim 1 in combination with a beta-lactamase inhibitor compound for treating a bacterial infection, or in combination with a beta-lactamase inhibitor compound in the manufacture of a medicament for treating a bacterial infection, wherein the beta-lactamase inhibitor compound is selected from thegroup consisting of relebactam, tazobactam. clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, zidebactam, enmetazobactam and durlobactam.

38. A process for preparing the crystalline hydrate form A of Claim 3 comprising the steps of:a) treating the compound of formula I with a solvent;b) stirring the mixture;c) centrifuging to provide a wet solid; andd) drying the wet solid to a low relative humidity to give a solid.

39. The process of Claim 36 wherein the solvent is pH 4 acetate buffer.

40. The process of Claim 36 wherein the mixture is stirred at a temperature of about 26 °C.

41. The process of Claim 36 wherein the solid is dried to a relative humidity between about 0% to about 33 %.

42. The process of Claim 36 wherein the solid is crystalline.

43. A process for preparing the crystalline hydrate form B of Claim 12 comprising the steps of:a) treating the compound of formula I with solvent;b) stirring the mixture;c) centrifuging to provide a wet slurry; andd) freeze drying the slurry to give a solid.

44. The process of Claim 41 wherein the solvent is pH 4 acetate buffer.

45. The process of Claim 41 wherein the mixture is stirred at a temperature of about 26 °C.

46. The process of Claim 41 wherein the slurry is freeze dried to a relative humidity greater than about 33% to less than about 41%.

47. The process of Claim 41 wherein the solid is cry stalline.

48. A process for preparing the crystalline hydrate form D of Claim 21 comprising the steps of:a) treating the compound of formula I form A and form B with acetate buffer;b) stirring the mixture;c) centrifuging to provide a wet slurry; andd) drying the wet slurry to provide a solid.

49. The process of Claim 46 wherein the acetate buffer is pH 4 acetate buffer.

50. The process of Claim 46 wherein the mixture is stirred at a temperature of about 26 °C.

51. The process of Claim 46 wherein the wet solid is dried to a relative humidity of about 55% or above.

52. The process of Claim 46 wherein the solid is cry stalline.

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