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Understanding colloidal speciation events of ASDs through advanced screening tools
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Biopharmaceutics Classification System (BCS) class II and IV drugs may be formulated as supersaturating drug delivery systems (e.g., amorphous solid dispersions [ASDs]). The mechanisms that contribute to the increased bioavailability of these systems are generally attributed to the increased solubility of the amorphous form but another mechanism, with significant contributions to the improved bioavailability has been recently identified. This mechanism is related with the formation of colloidal species that are able to improve the bioavailability several fold beyond that of the amorphous drug alone. These species occur when the concentration of drug generated in solution exceeds the amorphous solubility during dissolution, resulting in a liquid-liquid phase separation (LLPS).
This work intended to implement a screening methodology to understand the ability of a drug to form colloidal species in a biorelevant dissolution media. This screening strategy was therefore focused on following the colloidal formation of itraconazole (ITZ; model drug from BCS class II) in the presence of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) L, HPMC-AS M and HPMC-AS H (HPMC-AS with varying ratios of succinoyl:acetyl groups), using UV absorbance and a laser diffraction-based methodology. The ability of ITZ to form colloids by a solvent-shift approach was compared with the actual colloidal formation of ITZ amorphous solid dispersions produced by spray-drying (SDD). Results indicate that regardless of the used methodology to form supersaturated solutions of ITZ, colloids could be detected and monitored. The extension of colloid generation showed to be correlated with the SDD disintegration/dissolution rate, i.e, polymers with faster wettability kinetics led to faster SDD disintegration and colloidal formation.
As conclusion, this study showed that both laser diffraction and UV absorbance could give complementary information about colloidal formation and SDD dissolution profile, showing to be an excellent screening strategy to be applied in the early stage development of amorphous solid dispersions.
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Amorphous solid dispersion liquid-liquid phase separation colloids dissolution polymers screening tools