US 2011 O152311A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0152311 A1 Dedhiya et al. (43) Pub. Date: Jun. 23, 2011 (54) NOVEL CRYSTALLINE FORMS OF (30) Foreign Application Priority Data TRANS-7-OXO-6-(SULPHOOXY)-1,6- DIAZABICYCLO3.2.1]OCTANE-2-C Oct. 9, 2009 (FR) ....................................... O904864 ARBOXAMIDE SODUMI SALT Publication Classification (75) Inventors: Mahendra G. Dedhiya, Pomona, NY (US); Sisir Bhattacharya, (51) Int. Cl. Hauppauge, NY (US); Véronique A63L/439 (2006.01) DUCANDAS, VITRY SUR SEINE C07D 47/08 (2006.01) (FR); Alexandre GIULIANI, A6IP3L/04 (2006.01) VILLECRESNES (FR); Valérie (52) U.S. Cl. ......................................... 514/300; 54.6/121 RAVAUX, REYRIEUX (FR); Alain BONNET, CHATEAU-THIERRY (57) ABSTRACT (FR); Alain PRIOUR, PARIS (FR): The present invention relates to novel crystalline forms of Peter Lionel Spargo, DEAL (GB) Sodium salt of trans-7-oxo-6-(Sulphooxy)-1,6-diazabicyclo 3.2.1]octane-2-carboxamide (e.g., NXL-104) thereof. The (73) Assignee: FOREST LABORATORIES present invention relates to compositions comprising a crys HOLDINGS LTD., Hamilton (BM) talline form of sodium salt of trans-7-oxo-6-(sulphooxy)-1, (21) Appl. No.: 12/900,567 6-diazabicyclo3.2.1]octane-2-carboxamide (e.g., NXL 104) alone or in combination with an antibacterial agent (e.g., (22) Filed: Oct. 8, 2010 ceftaroline fosamil). Processes for the preparation of the crys talline forms and methods of treating bacterial infections by Related U.S. Application Data administering the crystalline forms alone or in combination (60) Provisional application No. 61/263,663, filed on Nov. with an antibacterial agent (e.g., ceftaroline fosamil) are also 23, 2009. described. Patent Application Publication Jun. 23, 2011 Sheet 1 of 6 US 2011/0152311 A1 5 10 15 20 25 30 35 40 Two-Theta (deg) Figure 1 Patent Application Publication Jun. 23, 2011 Sheet 2 of 6 US 2011/0152311 A1 2000.000 1800.000 - 1600.000 - 1400.000 - 1200.OOO - 1000.000 - 800,000 - 600,000 400.OOO 200.000 - 0.000 T - O.OOO 1 OOOO 20.OOO 30.000 40.000 50.000 2-theta (deg) Figure 2 Patent Application Publication Jun. 23, 2011 Sheet 3 of 6 US 2011/0152311 A1 16000.000 - 14000.000 - 12000.000 - 10000.000 - 8000.000 - 6000.000 - 4000.000 - 2000.000 - 0.000 0.000 10.000 20,000 30.000 40,000 50.000 60.000 2-theta (deg) Figure 3 Patent Application Publication Jun. 23, 2011 Sheet 4 of 6 US 2011/0152311 A1 6000.000 - 5000.000 - 4000.000 - 3000.000 - 2000.000 - 1OOO.OOO 0.000 - 0.000 1O.OOO 20.OOO 3O.OOO 40.OOO 50.000 60.000 2-theta (deg) Figure 4 Patent Application Publication Jun. 23, 2011 Sheet 5 of 6 US 2011/0152311 A1 3500.000 - 3000.000 - 2500.000 - 2000,000 - 1500.000 - 1OOOOOO - 500.000 - 0.000 - f t 0.000 10.000 20.000 30.000 40.000 50.000 2-theta (deg) Figure 5 Patent Application Publication Jun. 23, 2011 Sheet 6 of 6 US 2011/0152311 A1 1600.000 - 1400.000 - 1200.000 - 1000.000 - 800.000 - 600,000 - 400.000 - 200,000 - 0.000 - T 0.000 10,000 20.000 30.000 40.000 50,000 2-theta (deg) Figure 6 US 2011/0152311 A1 Jun. 23, 2011 NOVEL CRYSTALLINE FORMS OF 0005 U.S. Pat. No. 6,417,175 discloses compounds hav TRANS-7-OXO-6-(SULPHOOXY)-1,6- ing excellent antibacterial activities for a broad range of DIAZABICYCLO3.2.1]OCTANE-2- Gram-positive and Gram-negative bacteria. These com CARBOXAMIDE SODUMI SALT pounds are represented by the general formula: CROSS-REFERENCE TO RELATED APPLICATIONS 0001. This application claims priority under 35 U.S.C. S119, based on French Application No. 0904864 filed on Oct. 2 - - - - 39 9, 2009 and U.S. Provisional Application Ser. No. 61/263,663 NOR 3. 's, filed on Nov. 23, 2009, both of which are hereby incorporated N Y R by reference in their entirety. / y- O D a y FIELD OF THE INVENTION HN O a NS S 0002 The present invention relates to novel crystalline (OOO forms of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1 octane-2-carboxamide Sodium salt (e.g., NXL-104) and com positions comprising the crystalline forms alone or in com 0006 wherein R'-R, Q, X, Y and n areas defined therein. bination with an antibacterial agent (e.g., ceftaroline 0007 U.S. Pat. No. 6,417,175 discloses methods for pre fosamil). Processes for the preparation of the crystalline paring the compounds, and generically discloses formula forms and methods of treating bacterial infections by admin tions of the compounds, such as aqueous and Saline Solutions istering the crystalline forms alone or in combination with an for injection. One such compound is 7B-2(Z)-ethoxyimino antibacterial agent (e.g., ceftaroline fosamil) are also 2-(5-phosphonoamino-1,2,4-thiadiazole-3-yl)acetamido-3- described. 4-(1-methyl-4-pyridinio)-2-thiazolylhio-3-cephem-4-car BACKGROUND OF THE INVENTION boxylate. 0003 U.S. Pat. No. 7,112,592 discloses novel heterocyclic 0008 U.S. Pat. No. 6,906,055 discloses a chemical genus compounds and their salts, processes for making the com which includes compounds of formula: (HO)2PONH Sn N 21 " N CONH S N N No Nans O)S | O CHCH CO X nH2O pounds and methods of using the compounds as antibacterial 0009 Ceftaroline fosamil is a sterile, synthetic, parenteral agents. One Such compound is sodium salt of trans-7-OXO-6- prodrug cephalosporin antibiotic. The N-phosphonoamino (Sulphooxy)-1,6-diazabicyclo3.2.1]octane-2-carboxamide. water-soluble prodrug is rapidly converted into the bioactive ceftaroline, which has been demonstrated to exhibit antibac Application WO 02/10172 describes the production of azabi terial activity. Ceftaroline fosamil is known as (6R,7R)-7- cyclic compounds and salts thereof with acids and bases, and (2Z)-2-(ethoxyimino)-2-5-(phosphonoamino)-1,2,4-thia in particular, trans-7-OXO-6-sulphoxy-1,6-diazabicyclo3.2. diazol-3-yl)acetamido-3-4-(1-methylpyridin-1-ium-4- 1 octane-2-carboxamide and its pyridinium, tetrabutylam yl)-1,3-thiazol-2-yl)sulfanyl-8-oxo-5-thia-1-azabicyclo[4. monium and sodium salts. Application WO 03/063864 and 2.0oct-2-ene-2-carboxylate. Ceftaroline fosamil may be an U.S. Patent Publication No. 2005/0020572 describe the use of acetic acid hydrous form. compounds including trans-7-OXO-6-(Sulphooxy)-1,6-diaz SH: abicyclo3.2.1]octane-2-carboxamide sodium salt, as B-lac Nt tamase inhibitors that can be administered alone or in, com N1 O n1 | N bination with B-lactamine antibacterial agents. These O references are incorporated herein by reference, in their V 1 v. f N S entirety. HO OH S-N h N 0004 Ceftaroline is a novel parenteral cephalosporin with O abroad spectrum of activity against clinically important com N 21 -- munity-acquired and hospital-acquired Gram-negative and O Gram-positive pathogens including methicillin-resistant Sta O O CHCOOH HO phylococcus aureus and multidrug-resistant Streptococcus pneumoniae. US 2011/0152311 A1 Jun. 23, 2011 0010 U.S. Pat. No. 7,419,973 discloses compositions infections by administering the crystalline forms alone or in comprising ceftaroline fosamil and a pH adjuster, Such as, combination with an antibacterial agent (e.g., ceftaroline fos L-arginine. amil) are also described. 0011 U.S. Pat. Nos. 6,417,175 and 6,906,055 and 7,419, 973 are incorporated herein by reference, in their entirety. BRIEF DESCRIPTION OF THE FIGURES 0012. The present invention relates to the solid state physi (0019 FIG. 1 shows the powder X-Ray diffraction pattern cal properties of trans-7-OXO-6-(Sulphooxy)-1,6-diazabicy of amorphous trans-7-OXO-6-(Sulphooxy)-1,6-diazabicyclo clo3.2.1]octane-2-carboxamide Sodium salt (e.g., NXL 3.2.1]octane-2-carboxamide sodium salt (NXL-104). 104). These properties may be influenced by controlling the 0020 FIG. 2 shows the powder X-Ray diffraction pattern conditions under which trans-7-OXO-6-(Sulphooxy)-1,6-diaz of Form I of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3. abicyclo3.2.1]octane-2-carboxamide Sodium salt (e.g., 2.1]octane-2-carboxamide sodium salt (NXL-104). NXL-104) is obtained in solid form. 0021 FIG. 3 shows the powder X-Ray diffraction pattern 0013 Solid state physical properties include, for example, of Form II of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3. the flowability of the milled solid, rate of dissolution and 2.1]octane-2-carboxamide sodium salt (NXL-104). stability. The physical characteristics are influenced by the 0022 FIG. 4 shows the powder X-Ray diffraction pattern conformation and orientation of molecules in the unit cell, of Form III of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo which defines a particular crystalline form of a Substance. A 3.2.1]octane-2-carboxamide sodium salt (NXL-104). crystalline form may give rise to thermal behavior different (0023 FIG. 5 shows the powder X-Ray diffraction pattern from that of the amorphous material or another crystalline of Form IV of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo form. Thermal behavior is measured in the laboratory using 3.2.1]octane-2-carboxamide sodium salt (NXL-104). techniques such as capillary melting point, thermogravimet 0024 FIG. 6 shows the powder X-Ray diffraction pattern ric analysis (TGA) and differential scanning calorimetry of Form V of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.