Abstract

Biopharmaceutics Classification System (BCS) class II and IV drugs may be formulated as supersaturating drug delivery systems (e.g., amorphous solid dispersions [ASDs]) that can generate a supersaturated drug solution during gastrointestinal (GI) transit. The mechanisms that contribute to increased bioavailability are generally attributed to the increased solubility of the amorphous form, but another mechanism with significant contributions to the improved bioavailability have been recently identified. This mechanism consists on the formation of colloidal species and may further improve the bioavailability several fold beyond that of the amorphous drug alone. These colloidal species occur when the concentration of drug generated in solution exceeds the amorphous solubility during dissolution, resulting in a liquid-liquid phase separation (LLPS). For the appearance of LLPS, the crystallization kinetics needs to be slow relatively to the dissolution process. This work intended to implement an analytical methodology to understand the ability of a drug to form colloidal species in a biorelevant dissolution media. This screening tool was therefore focused on following the colloidal formation and crystallization kinetics of itraconazole (ITZ; model drug from BSC class II) in the presence of hydroxypropyl methylcellulose (HPMC-AS L and HPMC-AS M, which are HPMC-AS with varying ratios of succinoyl:acetyl groups), using 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. Results indicate that regardless of the used methodology, colloids of ITZ can be detected and monitored. The extension of colloid generation showed to be correlated with the ASD disintegration/dissolution rate, i.e, polymers with faster wettability kinetics led to faster ASD disintegration and colloidal formation.

As conclusion, this study showed that laser diffraction could give complementary information about colloidal formation and ASD 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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