Impact of degree of supersaturation on the dissolution and oral absorption behaviors of griseofulvin amorphous solid dispersions

Abstract

Although amorphous solid dispersion (ASD) is widely recognized as a formulation technology to improve oral absorption of poorly soluble drugs, prediction of its oral absorption behavior from in vitro dissolution tests is still difficult. This becomes especially challenging for drugs with high crystallization tendency, because crystallization during dissolution tests and in the gastrointestinal tract makes dissolution and precipitation behaviors complex. In this study, attempts were made to explain the oral absorption behavior of griseofulvin (GF), a drug with high crystallization tendency, from ASDs using in vitro supersaturation and dissolution tests with a focus on the effect of the degree of supersaturation. Liquid-liquid phase separation of a supersaturated GF solution in the presence of vinylpyrrolidone-vinyl acetate copolymer (PVPVA), Eudragit (Poly(methacrylic acid-co-methyl methacrylate)) L100-55 (Eudragit), or hydroxypropyl methylcellulose acetate succinate (HPMCAS) was investigated based on turbidity measurements to find that the apparent phase separation concentration was increased in the presence of all polymers. In both the dissolution test and oral absorption study, a significant effect of the degree of supersaturation was observed presumably because of high crystallization tendency of GF. Thus, dose setting in the dissolution test was important to achieve an in vitro-in vivo correlation of GF ASDs. Other conditions required for the in vivo predictive dissolution study included pH-shift and surfactant addition. The apparent liquid-liquid phase separation concentration also worked as a rough predictor of the oral absorption of GF from ASD.