In Vitro Characterization of Ritonavir Drug Products and Correlation to Human in Vivo Performance

Abstract

Ritonavir (RTV) is a weakly basic drug with a pH-dependent solubility. In vitro dissolution and supersatuation behaviors of three Norvir oral products including the tablet, powder, and solution were investigated by two biorelevant dissolution methods with pH alteration: a two-stage dissolution test and a biphasic dissolution-partition test. The two-stage dissolution test revealed a high degree of supersaturation of RTV from these products accompanied by the occurrence of liquid-liquid phase separation (LLPS) in biorelevant dissolution media. Higher, stable apparent RTV concentrations were observed in the FeSSIF-V2 as compared to those in the FaSSIF-V2, which suggested a food effect with higher exposure in the fed state. This is inconsistent with the evaluation in vivo. The biphasic test revealed significantly lower degrees of supersaturation of RTV in the aqueous media from these dosage forms as compared to results of the two-stage dissolution test. RTV concentrations in octanol at 6 h obtained from the tablet and powder with the use of the biorelevant media are consistent with corresponding in vivo AUC and Cmax under the fasting and moderate fat fed (MFF) states and predict the food effect. The underlying mechanisms responsible for the food effect are also proposed. Fractional partition profiles of RTV obtained in octanol from these three Norvir oral products are in agreement with the corresponding fractional absorption profiles in vivo under both the fasting and MFF states. This study reveals a complex interplay among the dissolution, precipitation, and partition processes from these formulations that dictate the oral exposure of RTV.

A Rational Design of a Biphasic Dissolution Setup—Modelling of Biorelevant Kinetics for a Ritonavir Hot-Melt Extruded Amorphous Solid Dispersion

“…Both described biphasic dissolution setups were assessed regarding their hydrodynamic [19]. The volumes of the aqueous phase and the mixing speed were set to 160 rpm for our method, while Xu et al used 60 rpm for an USP II/USP IV combination [33]. To visualize the velocity of the water, glitter powder (density 1.33 g/cm [38] was used.…”

“…The reference biphasic dissolution test for the present study basically consists of a combination of an USP II and an USP IV apparatus [12,33,39]. Initially, the ritonavir drug product disintegrates/dissolves in 41 mL SGF (pH = 1.6) in the flow-through cell (USP IV) at 5 mL/min for 30 min in a closed loop [33]). Later the closed loop is coupled with the USP II including 200 mL of FaSSIF-V2 and 200 mL of octanol.…”

“…The biphasic dissolution test runs for 6 h. The quantification in the organic layer was conducted by UV-Vis measurement using the second derivative, excluding interferences from formulation excipients or dissolution medium. Aqueous samples were quantified by HPLC after centrifugation [33]. The published data were extracted using Engauge Digitizer 10.9 [40].…”

“…The ODEs were iteratively calculated by a self-programmed LabView ® application. To describe and explain the concentration-time profiles resulting from BiPHa+ experiments appropriately, the kinetic model was advanced by introducing additional phase separation processes in the aqueous phase: (1) The formation of API-rich nano-droplets via liquid-liquid phase separation (LLPS) as described by Xu et al [33] for the same ritonavir-ASD, and (2) the process of transformation of the nanosized droplets to smaller particles, whereas the API remained amorphous [41]. Further details are given in Section 3.5.…”

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

“…This is especially an issue when surfactants are present in the media, such as in Level II biorelevant media containing bile salts and phospholipids [2], or in the formulation, which is typical for bio-enabling formulations. Many groups have studied biphasic dissolution experiments as a method to improve the predictive capabilities compared to single phase dissolution [3][4][5][6][7][8][9][10][11][12]. The majority of these experiments have been carried out using full scale dissolution apparatus.…”