Drug crystal growth in ternary amorphous solid dispersions: Effect of surfactants and polymeric matrix-carriers

Abstract

The present study evaluates the crystal growth rate of amorphous drugs when dispersed in different ternary polymeric amorphous solid dispersions (ASDs) in the presence of surfactants. Specifically, ternary ASDs of aprepitant (APT, selected as a model drug) were prepared via melt-quench cooling by evaluating three commonly used ASDs matrix/carriers, namely hydroxypropyl cellulose (HPC), poly(vinylpyrrolidone) (PVP) and the copolymer Soluplus® (SOL), and two suitable surfactants, namely d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly(ethylene glycol)- block -poly(propylene glycol)- block -poly(ethylene glycol) (P407). Results showed that all components were completely miscible (verified via hot stage polarized microscopy) and both surfactants were acting as plasticizers to the API. APT's crystal growth rate was increased in the presence of both P407 and TPGS, while PVP was identified as the matrix/carrier with the greatest impact API's crystal growth rate inhibition. Interestingly, TPGS presented a noticeable synergistic effect when combined with PVP resulting in a further reduction of APT's crystal growth rate. Furthermore, evaluation of APT's nucleation induction time in dissolution medium (PBS pH 6.8) revealed PVP as the most effective crystallization inhibitor, whereas the addition of TPGS showed to improve PVP's ability to inhibit APT's recrystallization. Finally, the formation of intermolecular interactions in the ternary APT-PVP-TPGS provided an explanation for the observed PVP-TPGS synergistic effects, with molecular dynamics simulations being able to unravel the type and extent of these interactions on a theoretical basis.

What Are the Important Factors That Influence API Crystallization in Miscible Amorphous API–Excipient Mixtures during Long-Term Storage in the Glassy State?

“…It should be noted that while most of the systems in Table are binary, it is important to understand interactions in ternary systems as well to ensure miscibility. A study of ternary ASDs with the API aprepitant, three polymers (HPC, PVP, and Soluplus), and two surfactants (TPGS and P407) investigated molecular interactions and crystallization inhibition in both binary and ternary combinations . It was verified that the ternary systems were miscible.…”

“…A study of ternary ASDs with the API aprepitant, three polymers (HPC, PVP, and Soluplus), and two surfactants (TPGS and P407) investigated molecular interactions and crystallization inhibition in both binary and ternary combinations. 61 It was verified that the ternary systems were miscible. Binary API combinations showed that the surfactants were acting as plasticizers to the API and that the API crystal growth rate was increased in the presence of both surfactants.…”

Recent Advances in Amorphous Solid Dispersions: Preformulation, Formulation Strategies, Technological Advancements and Characterization

“…Kapourani et al [ 88 ] manufactured ASD of BCS class IV drug Aprepitant using Soluplus ® , HPC, and PVP using HME. The authors have examined the effect of surfactants like Vit E TPGS and Poloxamer P 407 in inhibiting drug crystal growth in solid dispersion.…”

A lyophilized surfactant-based rutin formulation with improved physical characteristics and dissolution for oral delivery

“…Phase separation that leads to higher tendency of recrystallization of the active pharmaceutical ingredients (APIs) may be resulted from immiscible mixtures ( Pajula et al, 2014 , Luebbert and Sadowski, 2017 ). To predict the miscibility of the mixture, polarized microscopy is considered as the simplest to implement ( Kapourani et al 2021 ). With this technique, miscibility of the components in the formulation can be easily detected where miscible compounds will form a uniform optical pattern.…”