Modulating the solubility and pharmacokinetic properties of 5-fluorouracil via cocrystallization

Abstract

5-Fluorouracil (5FU) is a classical anti-metabolic drug with broad-spectrum antitumor effects. However, the oral absorption of 5FU is incomplete with a short biological half-life and an obvious peak-valley phenomenon, leading to the frequent administration requirement and severe side effects. Herein, a pharmaceutical cocrystallization approach based on crystal engineering was employed to modulate the pharmacokinetic properties of 5FU by changing its aqueous solubility. Four cocrystals of 5FU with a group of dihydroxybenzoic acids were synthesized and characterized. The powder dissolution experiments showed that all the cocrystals exhibited different aqueous solubilities and dissolution rates in comparison with pure 5FU. As compared to pure 5FU, the apparent solubility values of two cocrystals were increased by 34% and 11% while those of the other two cocrystals were reduced by 27% and 51%, respectively. The pharmacokinetic parameters of all the cocrystals, including C_max, t_max, MRT_0–t, t_1/2 and AUC_0–t, as well as the shape of the pharmacokinetic curves, were accordingly altered in the in vivo pharmacokinetic study. This study has important implications for using cocrystallization techniques to modulate the pharmacokinetic properties of drugs with undesirable oral absorption, especially to avoid the in vivo peak-valley effect and reduce side effects in clinical practice.