Relevance of Liquid-Liquid Phase Separation of Supersaturated Solution in Oral Absorption of Albendazole from Amorphous Solid Dispersions.

Kyosuke Suzuki,Michinori Oikawa,Takuya Fujita,Masafumi Fukiage,Maki Matsuda,Kohsaku Kawakami,Yohei Nishida

doi:10.3390/pharmaceutics13020220

Abstract

Amorphous solid dispersion (ASD) is one of the most promising formulation technologies for improving the oral absorption of poorly soluble drugs, where the maintenance of supersaturation plays a key role in enhancing the absorption process. However, quantitative prediction of oral absorption from ASDs is still difficult. Supersaturated solutions can cause liquid-liquid phase separation through the spinodal decomposition mechanism, which must be adequately comprehended to understand the oral absorption of drugs quantitatively. In this study, albendazole (ALZ) was formulated into ASDs using three types of polymers, poly(methacrylic acid-co-methyl methacrylate) (Eudragit) L100, Vinylpyrrolidone-vinyl acetate copolymer (PVPVA), and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The oral absorption of ALZ in rats administered as ASD suspensions was not explained by dissolution study but was predicted using liquid-liquid phase separation concentration, which suggested that the absorption of ALZ was solubility-limited. The oral administration study in dogs performed using solid capsules demonstrated the low efficacy of ASDs because the absorption was likely to be limited by dissolution rate, which indicated the importance of designing the final dosage form of the ASDs.

Highlights

Candidate compounds developed in the pharmaceutical industry frequently exhibit extremely low aqueous solubility and may be poorly absorbed after oral administration, which is one of the major issues in drug development
No crystalline diffraction peaks were observed for the Amorphous solid dispersion (ASD) prepared using Eudragit or hydroxypropyl methylcellulose acetate succinate (HPMCAS) (Figure 2c), whereas the PVPVA ASD showed small diffraction peaks at an ALZ:polymer ratio of 1:3
The diffraction peak disappeared when the PVPVA content was increased to a ratio of 1:4 (Figure 2c), which was confirmed in the polarized microscopy (PLM) image

Summary

Introduction

Candidate compounds developed in the pharmaceutical industry frequently exhibit extremely low aqueous solubility and may be poorly absorbed after oral administration, which is one of the major issues in drug development. For such compounds, supersaturating formulation technologies are often used to improve their oral absorption [1,2,3]. The method for predicting drugs’ oral absorption from supersaturating formulations using dissolution studies is still under debate [4]. Pharmaceutics 2021, 13, 220 active agents, including drug solubilization [9,10] and acceleration of crystalliza have complicated effects on the supersaturating dissolution behavior, which must considered. The dissolution test should be simple to ensure int vidual reproducibility

Methods

Results

Discussion

Conclusion