Effects of conformation of excipients succinic acid and maleic acid in molecular salts on in vitro/in vivo properties of marine drug cytarabine

A salification-actuated cocrystalline strategy has been proposed to allow full play to structural and property advantages of pharmaceutical excipients succinic acid (H 2 SA) and maleic acid (H 2 MA) in perfecting in vitro/vivo properties of marine antitumor drug cytarabine (ARC). Utilizing the acidity of H 2 SA/H 2 MA, and the alkalinity of ARC can generate strong charge-assisted complementary hydrogen-bond by proton transfer reaction, for one thing, it is conducive to protecting the amino active site of ARC and reducing its inactivation, eventually heightening the bioavailability. For another, the properties of ARC are raised by playing the superiorities of these excipients, thus increasing its therapeutic effect. Along this line, two new pharmaceutical molecular salts are achieved structurally characterized. The structure data display that both compounds are cytarabine monocarboxylate salt, namely HARC + -HAS – ( 1 ) and HARC + -HMA – ( 2 ), featuring with the charge-assisted hydrogen bonds. Thereinto, 1 has an open three-dimensional hydrogen-bonding skeleton, while 2 is closed into independent one-dimensional belts, which can ascribe to the configurations of these excipients. The structural features can regulate the poor permeability of ARC supported by theoretical and experimental data. While the meliorative properties have further promoted stronger antitumor activity and optimal pharmacokinetic behavior, with 2 showcasing greater superiority than that of 1 . These results offer new crystalline forms for ARC, also open an innovative avenue to the application of aliphatic diacid pharmaceutical excipients in the realm of marine antitumor drugs.