Lactam antibiotics and hydrates - the importance of crystallinity

A survey of crystalline hydrates of /3-lactams was recently reported in order to probe the significance of crystallinity on the stability of reactive APIs [54], Compounds which contain the /3-lactam core, including penicillin derivatives, carbapenems and cephalosporins, are known to undergo hydrolysis both in solution and in the solid state [55, 56], Solid-state stability has been shown to be dependent on storage conditions and degree of crystallinity [57-59]. It has also been shown that even hydrates of /3-lactams, where the water is regarded as a potential reactant, can be stable in the solid state for years. 

An example highlighting the impact of crystallinity on stability is that of meropenem (MERREM ), a trihydrate of a carbapenem antibiotic. Meropenem batches of different hydration states were examined for solid-state stability at 40 °C over a 1 month period [59]. An increase in amorphous content was shown to lead to a higher extent of and more rapid degradation in the solid state. However, the crystalline trihydrate exhibited a nearly 300-fold improvement in stability compared with a sample which was 80% amorphous. Similar observations have also been made on cephalosporin antibiotics as reported by Pikal and co-workers [58]. 

Crystalline hydrates of other electrophilic drugs other than /8-lactams have also been studied. The cases of neotame and aspartame illustrate a similar principle to the one exlemplifled by /8-lactams. The methyl esters are relatively stable in the solid state unless they are rendered amorphous [60, 61]. It is also true that in the case of neotame 

FiguK 3.6 Molecular structures of the native and ring open hydrolysed degradent of cefadroxil. Arrows highlight the hydrogen bonded water that is present in the crystal. The hydrolysis proceeds readily in aqueous solution but not in the crystalline hydrate 

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