Influence of Additives on the Properties of Nanodroplets Formed in Highly Supersaturated Aqueous Solutions of Ritonavir

Abstract

The formation of colloidal drug aggregates of lipophilic drugs is thought to be of relevance for the oral delivery of poorly water-soluble drugs. In this study, the underlying basis for colloid formation from amorphous solid dispersions and the impact of additives on colloidal stability were evaluated. A relationship was found between the concentration at which colloidal droplets formed upon dissolution of an amorphous solid dispersion and the liquid-liquid phase separation (LLPS) transition concentration, whereby the latter is related to the theoretical amorphous "solubility" value. The composition of the dispersed phase in ritonavir-polymer-water solutions was confirmed to be a noncrystalline, ritonavir-rich droplet phase. Additives were found to impact the size, stability, and crystallization behavior of the colloidal phase. In general, charged additives reduced the kinetics of droplet coalescence, but had a variable effect on crystallization kinetics, either promoting or inhibiting crystallization. Through proper selection of formulation components, it thus appears possible to promote the formation of ∼ 250-350 nm colloidal droplets of ritonavir following dissolution of an amorphous solid dispersion, and to inhibit coalescence and crystallization from these two-phase supersaturated solutions.

Physical chemistry of supersaturated solutions and implications for oral absorption

“…LLPS also has been observed in aqueous 443 solutions during the evaluation of solubility enhancing formulations 444 [39][40][41][42]. The drug-rich species formed following LLPS typically have a 445 size of 100-500 nm when characterized immediately after formation 446 using a technique such as dynamic light scattering [29,39,40,43].…”

Impact of Endogenous Bile Salts on the Thermodynamics of Supersaturated Active Pharmaceutical Ingredient Solutions

“…24 However, given the good agreement between the three methods, it is apparent that the system does not undergo substantial supersaturation with respect to GLPS in agreement with previous observations. 25,26 Figure 4 shows an example of the UV extinction experiment of telaprevir in 50mM pH 6.5 phosphate buffer, in which the onset of GLPS is indicated by increased light scattering due to the spontaneous formation of a drug-rich phase in the solution when the concentration exceeds a certain value. By subsequently separating the drug-rich dispersed phase from the continuous phase, using ultracentrifugation to pellet the drug-rich phase, the composition of the continuous phase can be determined, thereby yielding one of the binodal points (at 37°C).…”

Impact of Solubilizing Additives on Supersaturation and Membrane Transport of Drugs

“…2 (20,21,27). However, the influence of solubilizing additives on both the maximum achievable flux and the tendency of the system to undergo LLPS has not been widely explored.…”

“…In addition, at very high supersaturations, a non-crystalline drug-rich may be formed (17)(18)(19). Formation of a disordered drug-rich phase has been widely observed during dissolution of amorphous solid dispersions (20)(21)(22)(23)(24)(25)(26). Certain polymers are believed to facilitate formation of this disordered phase by inhibiting crystallization and can stabilize the resultant drugrich phase in the nano-sized regime (23,24).…”