The antitumour drug 7-ethyl-10-hydroxycamptothecin monohydrate and its solid-state hydrolysis mechanism on heating

7‐Ethyl‐10‐hydroxycamptothecin [systematic name: (4S)‐4,11‐diethyl‐4,9‐dihydroxy‐1H‐pyrano[3′,4′:6,7]indolizino[1,2‐b]quinoline‐3,14(4H,12H)‐dione, SN‐38] is an antitumour drug which exerts activity through the inhibition of topoisomerase I. The crystal structure of SN‐38 as the monohydrate, C22H20N2O5·H2O, reveals that it is a monoclinic crystal, with one SN‐38 molecule and one water molecule in the asymmetric unit. When the crystal is heated to 473 K, approximately 30% of SN‐38 is hydrolyzed at its lactone ring, resulting in the formation of the inactive carboxylate form. The molecular arrangement around the water molecule and the lactone ring of SN‐38 in the crystal structure suggests that SN‐38 is hydrolyzed by the water molecule at (x, y, z) nucleophilically attacking the carbonyl C atom of the lactone ring at (x − 1, y, z − 1). Hydrogen bonding around the water molecules and the lactone ring appears to promote this hydrolysis reaction: two carbonyl O atoms, which are hydrogen bonded as hydrogen‐bond acceptors to the water molecule at (x, y, z), might enhance the nucleophilicity of this water molecule, while the water molecule at (−x, y + , −z), which is hydrogen bonded as a hydrogen‐bond donor to the carbonyl O atom at (x − 1, y, z − 1), might enhance the electrophilicity of the carbonyl C atom. The crystal structure of 7‐ethyl‐10‐hydroxycamptothecin monohydrate suggests that the hydrogen‐bond network around the water molecule and the lactone ring promotes the hydrolysis reaction in the crystal.