Hypercholesterolemia is one of the independent risk factors for the development of cardiovascular diseases such as atherosclerosis. The treatment of hypercholesterolemia is of great significance to reduce clinical cardiovascular events and patient mortality. Simvastatin (SIM) and ezetimibe (EZE) are commonly used clinically as cholesterol-lowering drugs; however, their treatment efficacy is severely affected by their poor water solubility and low bioavailability. In this study, SIM and EZE were made into a co-amorphous system to improve their dissolution, oral bioavailability, storage stability, and cholesterol-lowering effects. The SIM-EZE co-amorphous solids (CO) were prepared successfully using the melt-quenched technique, and the physicochemical properties of CO were characterized accordingly, which exhibited improved physical stability and faster dissolution release profiles than their physical mixture (PM). In the pharmacokinetic study, the SIM-EZE CO or PM was given once by oral gavage, and mouse blood samples were collected retro-orbitally at multiple time points to determine the plasma drug concentrations. In the pharmacodynamic study, low-density lipoprotein receptor-deficient (LDLr−/−) mice were fed with a high-fat diet (HFD) for two weeks to establish a mouse model of hypercholesterolemia. Using PM as a control, we investigated the regulation of CO on plasma lipid levels in mice. Furthermore, the mice feces were collected to determine the cholesterol contents. Besides, the effect of EZE on the NPC1L1 mRNA expression level in the mouse intestines was also investigated. The pharmacokinetics results showed that the SIM-EZE CO has improved bioavailability compared to the PM. The pharmacodynamic studies showed that SIM-EZE CO significantly increased the cholesterol-lowering effects of the drugs compared to their PM. The total cholesterol excretion in the mouse feces and inhibitory effect on NCP1L1 gene expression in the mouse intestines after being given the SIM-EZE CO were more dramatic than the PM. Our study shows that the SIM-EZE CO prepared by the melt-quenched method can significantly improve the stability, bioavailability, and cholesterol-lowering efficacy with excellent development potential as a new drug formulation.

Surfactants have been widely used as effective additives to increase the solubility and dissolution rates of amorphous solid dispersions (ASDs). However, they may also generate adverse effects on the physical stability of ASDs. In this study, we systematically investigated the impacts of poloxamer, a frequently used surfactant, on the crystallization of amorphous clotrimazole (CMZ). The added poloxamer significantly decreased the glass transition temperature (Tg) of CMZ and accelerated the growth of Form 1 and Form 2 crystals. It was found that the poloxamer had an accelerating effect on Form 1 and Form 2 but showed a larger accelerating effect on Form 1, which resulted from a combined effect of increased mobility and local phase separation at the crystal–liquid interface. Additionally, the added poloxamer exhibited different effects on nucleation of the CMZ polymorphs, which was more complicated than crystal growth. The nucleation rate of Form 1 was significantly increased by the added poloxamer, and the effect increased with increasing P407 content. However, for Form 2, nucleation was slightly decreased or unchanged. The nucleation of Form 2 may have been influenced by the Form 1 crystallization, and Form 2 converted to Form 1 during nucleation. This study increases our understanding of poloxamer and its impacts on the melt crystallization of drugs.

Clotrimazole (CMZ) is a classical antifungal drug for studying crystallization. In this study, a new CMZ polymorph (Form 2) was discovered during the process of nucleation and growth rate determination in the melt. High-quality single crystals were grown from melt micro droplets to determine the crystal structure by X-ray diffraction. Form 2 is metastable and exhibits a weathercock-type disordered structure. The crystal nucleation and growth kinetics of the two CMZ polymorphs were systematically measured. The maximum nucleation rate of Form 1 and 2 was observed at 50 ℃ (1.07 T_g). Form 2 nucleates and grows faster than the existing form (Form 1). The polymorphic composition can be switched by changing the relative kinetics of crystal nucleation and growth through varying the temperature. This study is relevant for the discovering new drug polymorphs through an understanding of nucleation and growth kinetics during melt crystallization.