Comparison of induction methods for supersaturation: Amorphous dissolution versus solvent shift

Simple solvent shift is often used to induce supersaturation and investigate precipitation kinetics in early drug development as a substitute for amorphous dissolution. This study develops and compares a small-scale non-sink amorphous dissolution method to a solvent shift method as induction methods for supersaturation of the model drugs albendazole, felodipine and tadalafil with respect to the maximum dissolved drug concentration, and the solid form of the precipitate.

The study also investigates the effect of pre-dispersed precipitation inhibitors (hydroxypropyl methyl cellulose (HPMC) or polyvinylpyrrolidone (PVP)) on tadalafil supersaturation induced by both amorphous dissolution and solvent shift with respect to maximum dissolved drug concentration, precipitation rate and solid form of the precipitate. The maximum drug concentrations achieved through solvent shift were 15.9, 208 and 108 µg/mL for albendazole, felodipine and tadalafil, respectively. Pre-dispersing 0.1% (w/v) HPMC or PVP, increased the maximum concentration by solvent shift of tadalafil to 180 µg/mL, for both polymers. Dissolution of up to 90 mg albendazole, 120 mg felodipine and 8.9 mg tadalafil could yield a maximum dissolved drug concentration of 76.1%, 87.9% and 102.5%, respectively, of the corresponding solvent shift maximum concentration.

The maximum concentration achieved through amorphous dissolution of tadalafil with HPMC or PVP present in the dissolution medium was 87.1% and 88.7%, respectively of the solvent shift maximum concentration. Dissolution of 2 mg amorphous tadalafil with and without pre-dispersed polymer gave the same rank order of onset of precipitation as for the solvent shift method. The solid form of precipitate was the same for albendazole, felodipine, tadalafil and tadalafil with PVP for both methods. For tadalafil with HPMC, the precipitate was amorphous following solvent shift, but crystalline after amorphous dissolution.

Overall, this study shows that the maximum concentration achievable through amorphous dissolution can be estimated when performing solvent shift and the precipitation inhibition of excipients assessed via solvent shift can be used to predict the effect on precipitation using amorphous dissolution. More on induction of supersaturation