Pharmaceutical Cocrystals Of Diethylstibestrol

As a new solid form,cocrystal has attracted considerable attention from both the academic and pharmaceutical industry fields in recent years.Now cocrystal takes an important part in the pre-prescription research stage.Compared with other solid forms（such as amorphous,polymorphs,solvates,salts,etc.）,pharmaceutical cocrystals can be designed and synthesized on the basis of supramolecular chemistry and crystal engineering principles.Pharmaceutical cocrystals could improve the physicochemical properties,maintain the pharmacological activity and also ensure the safety and clinical curative effect of the drug without the formation or destruction of covalent bond.Diethylstilbestrol（DES）is an important synthetic non-steroidal estrogen,but its clinical application is greatly limited by its poor compliance,drug accumulation,and low bioavailability.This research aimed to modulate the pharmacokinetic properties of DES via changing the dissolution rate through cocrystallization.Cocrystals of DES were designed through pyridine phenol and carboxyl-phenol synthons.Fourteen cocrystals as well as their single crystal structures were discovered.All of these cocrystals were systematically characterized,and the intrinsic dissolution rate（IDR）for the eight pharmaceutical cocrystals of DES were investigated in pH 2.0 buffer solution.Two assumptions(enhance C_max or prolong T_max)with the aim of improving compliance were put forward.On the basis of the IDR results（DES-NIA with 1.5-fold increase and DES-2FLA-B with 5.5-fold decrease）and the pharmacological activities of coformers（NIA and FLA with CYPs inhibition and UGTs stimulation effects）,the pharmacokinetic behaviors of these two cocrystals were further researched.The 2-fold prolongation of T_max in the PK profile DES-2FLA-B facilitated the improvement of compliance.This research not only has guiding significance for the design and application of pharmaceutical cocrystals,but also has reference value for improving the physicochemical and pharmacokinetic properties of drugs via cocrystallization.