Sodium Lauryl Sulfate Competitively Interacts with HPMC-AS and Consequently Reduces Oral Bioavailability of Posaconazole/HPMC-AS Amorphous Solid Dispersion

Abstract

Sodium lauryl sulfate (SLS), as an effective surfactant, is often used as a solubilizer and/or wetting agent in various dosage forms for the purpose of improving the solubility and dissolution of lipophilic, poorly water-soluble drugs. This study aims to understand the impact of SLS on the solution behavior and bioavailability of hypromellose acetate succinate (HPMC-AS)-based posaconazole (PSZ) ASDs, and to identify the underlying mechanisms governing the optimal oral bioavailability of ASDs when surfactants such as SLS are used in combination. Fluorescence spectroscopy and optical microscopy showed that "oil-out" or "liquid-liquid phase separation (LLPS)" occurred in the supersaturated PSZ solution once drug concentration surpassed ∼12 μg/mL, which caused the formation of drug-rich oily droplets with initial size of ∼300-400 nm. Although FT-IR study demonstrated the existence of specific interactions between PSZ and HPMC-AS in the solid state, predissolved HPMC-AS was unable to delay LLPS of the supersaturated PSZ solution and PSZ-rich amorphous precipitates with ∼16-18% HPMC-AS were formed within 10 min. The coprecipitated HPMC-AS was found to be able to significantly delay the crystallization of PSZ in the PSZ-rich amorphous phase from less than 10 min to more than 4 h, yet coexistent SLS was able to negate this crystallization inhibition effect of HPMC-AS in the PSZ-rich amorphous precipitates and cause fast PSZ crystallization within 30 min. 2D-NOESY and the CMC/CAC results demonstrated that SLS could assemble around HPMC-AS and competitively interact with HPMC-AS in the solution, thus prevent HPMC-AS from acting as an effective crystallization inhibitor. In a crossover dog PK study, this finding was found to be correlating well with the in vivo bioavailability of PSZ ASDs formulated with or without SLS. The SLS containing PSZ ASD formulation demonstrated an in vivo bioavailability ∼30% of that without SLS, despite the apparently better in vitro dissolution, which only compared the dissolved drug in solution, a small fraction of the total PSZ dose. We conclude that the bioavailability of ASDs is highly dependent on the molecular interactions between drug, surfactant, and polymer, not only in the solution phase but also in the drug-rich "oily" phase caused by supersaturation.

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

“…In these particles, polymers were able to inhibit crystallization (Ueda et al, 2017). Similar results were demonstrated in a study of a posaconazole-HPMC-AS system (Chen et al, 2016b).…”

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance

“…10,13 Drug-polymer interaction also plays an important role during the dissolution process of ASDs. 19,23,24 Therefore, the molecular interaction between BMS-817399 and PVP was firstly studied using FT-IR.…”

Spray-Dried Amorphous Solid Dispersions of Griseofulvin in HPC/Soluplus/SDS: Elucidating the Multifaceted Impact of SDS as a Minor Component

“…Moreover, the presence of a surfactant in the ASD formulation could increase wettability of the relatively hydrophobic drug [17,18], while it can also inhibit drug precipitation in the aqueous medium [19,20]. On the contrary, other studies [21][22][23][24] have suggested that surfactants negatively affected drug release from ASDs due to the competitive interaction between the drug-polymer-surfactant, resulting in drug recrystallization promotion from the supersaturated solutions. Therefore, to say the least, the impact and roles of surfactants in the dissolution of drug ASDs are complex and somewhat elusive, and the use of surfactants can be detrimental or beneficial depending on the specific drug-polymer-surfactant system and composition.…”