A rational design of a biphasic dissolution setup—modelling of biorelevant kinetics for a ritonavir hot-melt extruded amorphous solid dispersion

Abstract

Biphasic dissolution systems achieved good predictability for the in vivo performance of several formulations of poorly water‐soluble drugs by characterizing dissolution, precipitation, re-dissolution, and absorption. To achieve a high degree of predictive performance, acceptor media, aqueous phase composition, and the apparatus type have to be carefully selected. Hence, a combination of 1‐decanol and an optimized buffer system are proposed as a new, one‐vessel biphasic dissolution method (BiPHa+). The BiPHa+ was developed to combine the advantages of the well‐described biorelevance of the United States Pharmacopeia (USP) apparatus II coupled with USP apparatus IV and a small‐scale, one‐vessel method. The BiPHa+ was designed for automated medium addition and pH control of the aqueous phase. In combination with the diode array UV-spectrophotometer, the system was able to determine the aqueous and the organic medium simultaneously, even if scattering or overlapping of spectra occurred. At controlled hydrodynamic conditions, the relative absorption area, the ratio between the organic and aqueous phase, and the selected drug concentrations were identified to be the discriminating factors. The performance of a hot‐melt extruded ritonavir‐containing amorphous solid dispersion (ritonavir‐ASD) was compared in fasted‐state dissolution media leading to different dissolution‐partitioning profiles depending on the content of bile salts. An advanced kinetic model for ASD‐based well described all phenomena from dispersing of the ASD to the partitioning of the dissolved ritonavir into the organic phase.