Improving Compliance and Decreasing Drug Accumulation of Diethylstilbestrol through Cocrystallization

Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, has been prescribed for advanced breast cancer and prostate cancer. However, its poor compliance, reactive metabolite toxicity and hydrophobicity-induced drug accumulation has limited its applications. In this study, we aimed to modulate its dissolution rate and reduce reactive metabolites and drug accumulation through cocrystallization. Cocrystals of DES with isonicotinamide (INA), picolinamide (PIN), nicotinamide (NIA), urea (UREA), sarcosine (SAR), and flavone (FLA) were obtained. Different crystallization strategies result in cocrystal polymorphs for DES with INA and FLA. Intrinsic dissolution rate (IDR) characterizations in pH 2.0 buffer solution were conducted. Two assumptions (enhancing Cmax or prolonging Tmax) with the aim of improving compliance were put forward. On the basis of the IDR results (DES-NIA with a 1.5-fold increase in IDR and DES-2FLA-B with a 5.5-fold decrease in IDR) and the pharmacological activities of coformers (NIA an...