Cephalexin: a channel hydrate

Abstract

The antibiotic cephalexin [systematic name: d-7-(2-amino-2-phenylacetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid] forms a range of isomorphic solvates, with the maximum hydration state of two water molecules formed only at high relative humidities. The water content of the structure reported here (C 16 H 17 N 3 O 4 SÁ1.9H 2 O) falls just short of this con®guration, having three independent cephalexin molecules, one of which is disordered, and 5.72 observed water molecules in the asymmetric unit. The facile nature of the cephalexin solvation/desolvation process is found to be facilitated by a complex channel structure, which allows free movement of solvent in the crystallographic a and b directions. CommentThe cephalosporin derivative cephalexin (CEX) is an antibiotic useful for treating a variety of infections, including those of the respiratory tract, of the skin and of other soft tissues. The characterization of the solid-state properties of CEX has, however, been hampered by uncertainty over the exact nature of its hydration behaviour. CEX can form a range of hydrates in the solid state, all with essentially identical unit cells, and has thus been identi®ed as part of the class of compounds known as isomorphic desolvates (Stephenson et al., 1998). Indeed, CEX is known to go further and reversibly replaces water with other small, polar, solvent molecules (Pfeiffer et al., 1970). Powder diffraction studies show that the isomorphic solvates have similar unit-cell dimensions but, despite their crystallographic similarities, their commercially important physical properties (such as their solubilities and dehydration behaviour) vary considerably. Despite considerable interest in CEX, no single-crystal structure determination had previously been achieved, and so the structural basis of its ready solvation/desolvation process remained unknown. However, we have overcome the problems of small crystal size and loss of (single) crystallinity upon facile dehydration by utilizing careful sample preparation methods (see Experimental) and the extra intensity of synchrotron radiation to report here the ®rst crystal structure of any CEX hydrate, that of CEXÁ1.9H 2 O, (I).The asymmetic unit of (I) was found to contain three CEX molecules and, spread over ten sites, 5.72 water molecules. The three crystallographically independent molecules of CEX (Fig. 1) were found to exist in the zwitterionic form, with no signi®cant differences in their bond lengths or angles. One CEX molecule is disordered. There is some¯exibility in the amide backbone, with the OÐCÐCÐN(H 3 ) torsion angles ranging from 27.3 (6) to 44.5 (6) . The geometry of the related species cefadroxil (Shin & Cho, 1992) has a similar conformation, ®tting within the range found here for CEX, as does CEX complexed with -napthol (Kemperman et al., 1999), although here the amide backbone is more eclipsed (equivalent angle = 16.2 ).That the stochiometrically exact dihydrate is not found is unsurprising, given the steep gradient observed by Ste...

X-ray and Neutron Diffraction in the Study of Organic Crystalline Hydrates

“…Larger channels are more likely to be a structural feature of non-stoichiometric hydrates, as the water can diffuse more easily through these channels without the general structure changing. Cephalexin dihydrate [43] shows such large channels along the a-axis. The water molecules are mostly disordered indicating already the higher mobility than in caffeine or theophylline.…”

Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria

“…In pharmaceutical preparations, monohydrated cephalexin is the predominant polymorphic form (Aguiar et al, 2011). Cephalexin is also found in the dihydrated form, which, at room temperature, rapidly loses one molecule of water to form the monohydrated cephalexin (Kennedy et al, 2003). A similar phenomenon occurs with erythromycin, which is commercialized in its more stable and less soluble dihydrated form.…”

“…In addition to being easily controllable, the more stable polymorphic form also complies with requirements described in the Q6A Guide of the International Commission on Harmonization (ICH) for solid form selection (Grant et al, 2004). Kristl et al, 1996;Sohn et al, 2008;Lutker et al, 2011;Tutughamiarso et al, 2012) Acetylsalicylic Acid Analgesic IV 2 I (TSRL inc, 2012; Klein et al, 1994;Vishweshwar et al, 2005;Bond et al, 2011) Ibuprofen Analgesic II 2 I (TSRL inc, 2012;Shankland et al, 1996;Erk et al, 2004;Stone et al, 2009;Derollez et al, 2010) Acetaminophen Analgesic IV 6 I (TSRL inc, 2012;Haisa et al, 1974;Naumov et al, 1998;McGregor et al, 2002;Parkin et al, 2002;Peterson et al, 2002;Fabbiani et al, 2004 (Otsuka et al, 1983;Stephenson et al, 1998;Kennedy et al, 2003;Kasim et al, 2004;Aguiar et al, 2011) Ciprofloxacin Antibiotic III 3 II (hydrate) (TSRL inc, 2012;Turel et al, 2003;Fabbiani et al, 2008;Fabbiani et al, 2009;Fabbiani et al, 2011) Doxycycline Antibiotic IV 2 ‡ (TSRL inc, 2012; Legendre et al, 2012) Erythromycin Antibiotic IV 4 Dihydrate (TSRL inc, 2012;Fukumori et al, 1983;Stephenson et al, 1997;Miroshnyk et al, 2006) Sulfamethoxazole Antibiotic IV 4 III (hemihydrate) (TSRL inc, 2012;…”

Invariom modeling of ceftazidime pentahydrate: molecular properties from a 200 second synchrotron microcrystal experiment

“…Singlecrystal X-ray structures of cephalosporins are commonly of low quality, probably due to disorder caused by the conformational flexibility of the cephem ring structure or a lack of matching intermolecular interactions. The tendency of several cephalosporins to form solvates, co-crystals and channel structures (Kemperman et al, 1999(Kemperman et al, , 2000(Kemperman et al, , 2001Stephenson & Diseroad, 2000;Kennedy et al, 2003) is probably also related to the flexibility of the cephem ring. Consequently, several cephalosporin structures remain unknown, and despite the importance of cephalosporins in the market not many structures have been determined to a high accuracy.…”