Direct Observation of Nanostructures during Aqueous Dissolution of Polymer/Drug Particles

Abstract

To elucidate the aqueous solubility enhancement mechanism of solid dispersions (SDs), metastable blends of an active pharmaceutical ingredient (API) and a polymer excipient, we investigated the dissolution of hydroxypropyl methylcellulose acetate succinate (HPMCAS) SDs in phosphate buffered saline (PBS). Two hydrophobic active pharmaceutical agents, phenytoin and probucol, were employed at loadings of 10, 25, and 50 wt % relative to polymer. Light scattering measurements of HPMCAS solutions showed that the polymer itself formed a mixture of ∼10 and ∼100 nm sized structures (attributed to linear and covalently coupled polymer chains, respectively) in both tetrahydrofuran and PBS. The measurements also revealed that PBS is a poor solvent for HPMCAS at and below 37 °C, potentially inducing the polymer to associate with itself or other hydrophobic species in solution. During in vitro dissolution of HPMCAS SDscontaining either phenytoin or probucol as the APIthe polymer and hydrophobic drug formed <100 nm amorphous nanoparticles. Using a combination of cryogenic transmission electron microscopy (both imaging and electron diffraction) and small-angle X-ray scattering, a direct correlation between SD dissolution profiles and nanostructure evolution was discovered for both drugs. In other words, the drug that is measured in the dissolution assay is retained in the supernatant in the form of nanoparticles. The size, shape, and lifespan of the nanoparticles were a function of drug identity, loading, and targeted concentration. These findings confirm the importance of persistent nanostructures to SD dissolution and particularly to maintenance of supersaturation.

Using Acetone/Water Binary Solvent to Enhance the Stability and Bioavailability of Spray Dried Enzalutamide/HPMC-AS Solid Dispersions

“…36 Similar morphology is reported in other work where binary mixture was used. 37 During a spray drying process, it was suggested that liquid droplets could shrink in an isotropic manner, whereby both chemical nature and viscosity of the solvent determine the corresponding mass transfer kinetics. Upon the evaporation of the solvent, drug and polymer mixture would thicken and form a primary shell.…”

Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles

“…This effect was also determined to be a prerequisite for the formation of drug-rich nanoparticles. Ricarte et al directly observed nanoparticles during the dissolution of phenytoin and probucol with HPMCAS by utilizing cryogenic transmission electron microscopy (cryo-TEM) and small-angle X-ray scattering (SAXS) . They found that the drug concentration profile could be directly related to the number density of nanoparticles, and that properties such as drug identity, loading, and targeted drug concentration affected particle formation.…”

Polymer Nanogels as Reservoirs To Inhibit Hydrophobic Drug Crystallization

“…Due to the centrifugation procedure in the in vitro dissolution assay, the apparent drug concentration reflects drugs that are either molecularly dissolved or retained in the supernatant within the nanoparticles ( i . e ., ≤ 100 nm), which are presumably bioavailable for oral absorption. − The equilibrium solubility of crystalline phenytoin in PBS/FaSSIF solution at 22 °C (27 ± 1 μg/mL) was previously reported and is indicated by the dashed line in Figure . The target phenytoin concentration was 1000 μg/mL; such a high supersaturation results in a strong thermodynamic driving force for drug nucleation and crystal growth …”