Formation mechanism of amorphous drug nanoparticles using the antisolvent precipitation method elucidated by varying the preparation temperature.

Abstract

The present study focuses on the effect of the preparation temperature on the physicochemical properties of amorphous drug nanoparticles to clarify their formation mechanism. Amorphous glibenclamide (GLB) nanoparticles were prepared at 4-40 °C using two antisolvent precipitation methods. In method A, N,N-dimethylformamide (DMF) solution of GLB was added to an aqueous solution containing hydroxypropyl methylcellulose (HPMC) to obtain nano-A suspensions. In method B, nano-B suspensions were obtained by adding DMF solution containing both GLB and HPMC into water. When the preparation temperature was above 25 °C, nano-A and nano-B showed similar HPMC compositions. However, nano-B contained a large amount of HPMC compared to nano-A at temperatures below 20 °C. The glassy nature of the nanoparticle cores restricts the diffusion of HPMC from amorphous GLB nanoparticles to the aqueous phase, indicating that the glass transition temperature (Tg) of neat amorphous GLB (73 °C) would be considerably decreased owing to the nanosizing and water sorption of amorphous GLB. The physical stability of amorphous GLB nanoparticles was improved with increased HPMC in the nanoparticles. Thus, setting the preparation temperature by considering the Tg of the antisolvent-saturated amorphous drug nanoparticles is essential to develop stable amorphous drug nanoparticles.