Amorphous solid dispersion enhances permeation of poorly soluble ABT-102: True supersaturation vs. apparent solubility enhancement

Abstract

Amorphous solid dispersions (ASDs) represent a promising formulation approach for poorly soluble drugs. We explored the formulation-related impact of ASDs on permeation rate, apparent solubility and molecular solubility of the poorly soluble drug ABT-102. The influence of fasted state simulated intestinal fluid (FaSSIF) as dispersion medium was also studied. ASDs were prepared by hot-melt extrusion. Permeation rate was assessed by the Caco-2 transwell assay. Cell viability and barrier integrity were assured by AlamarBlue©, TEER and permeability of the hydrophilic marker carboxyfluorescein. Apparent solubility and molecular solubility were evaluated by using centrifugation and inverse dialysis, respectively. The in vitro permeation rate of ABT-102 from aqueous dispersions of the ASD was found 4 times faster than that from the dispersions of the crystals, while apparent solubility and molecular solubility of ABT-102 were increased. Yet, a further increase in apparent solubility due to micellar solubilization as observed when dispersing the ASD in FaSSIF, did not affect molecular solubility or permeation rate. Overall, a good correlation between permeation rate and molecular solubility but not apparent solubility was seen.

Influence of hydrophilic additives on the supersaturation and bioavailability of dutasteride-loaded hydroxypropyl- β-cyclodextrin nanostructures

“…10 Supersaturatable dosage forms improve the solubility and oral bioavailability of water-insoluble drugs, and are now being widely explored in the pharmaceutical industry. [11][12][13][14][15] Amorphous solid dispersion and lipid-based formulations (eg, the supersaturatable self-microemulsifying drug delivery system) containing polymeric precipitation inhibitors are regarded as supersaturatable formulations. The supersaturated state is a thermodynamically unstable amorphous form and eventually reverts to a stable state because of drug precipitation.…”

Improved oral bioavailability of poorly water-soluble glimepiride by utilizing microemulsion technique

“…However, recent studies have shown that enhanced apparent solubility, which is because of micellarization or complexation, does not induce an enhanced permeation rate of a poorly soluble drug in vitro. 26,[40][41][42][43][44] The solubility-permeability interplay cannot be ignored when using solubility-enabling formulations. 45,46 As mentioned earlier, we can draw a conclusion that increasing drug solubility utilizing pharmaceutical techniques does not necessarily lead to improved bioavailability.…”

“…This result is consistent with the previous literature. 43,44 Compared to GM solubility in water (1.6 µg/mL), the solubility of an optimized GMME formulation increased up to 340 times (544.6±4.91 µg/mL). Meanwhile, a noticeable enhancement in GM dissolution was observed in the GM-MU complex -the solubility of GM was found to increase up to 24,000 times.…”

The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility

“…The angle range was chosen for the indication of crystallinity of ABT-102, because a previous study showed that crystalline ABT-102 showed its biggest reflex in that range. 13 FT-IR studies of the dried precipitate were done to determine the ingredients of the amorphous microparticles. Figure 8 presents the spectra of the single compounds and of the precipitate (microparticles).…”