No abstract

The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loading facilitated desupersaturation. Sol was the only effective nucleation inhibitor; the overall precipitation inhibition capability was ranked: Sol > HPMC > VA64. In the dissolution tests, only the Sol-based ASDs generated significant supersaturation, which decreased upon an increase in the nanoseed loading. This study has demonstrated the importance of using drug nanocrystals in lieu of conventional coarse crystals in desupersaturation and dissolution tests in ASD development.

Nano-sized drug particle formation is one of the most popular approaches in dissolution enhancement of poorly water-soluble drugs. However, it requires process optimization since it is a time consuming and costly method. The aim of this study is to investigate the impact of various mixtures of crosslinked polystyrene (CPS) and yttrium-stabilized zirconia (YSZ) beads (YSZ:CPS = 0:100-100:0 %v:%v) on the breakage kinetics and energy consumption during the wet stirred media milling (WSMM) of fenofibrate (FNB, BCS II drug). Five WSMM experiments were conducted using 3000 rpm stirrer speed and 50% volumetric bead loading with a suspension of 10% FNB, 7.5% HPC-L, and 0.05% SDS. Laser diffraction was used for the determination of particle sizes. Breakage rate, power required by the mill, and specific energy consumption were analyzed for all mixture runs. The experimental data show that YSZ beads provided faster breakage than the CPS beads, as signified by the lower time constant of the former. On the other hand, CPS beads required lower stirrer power than the YSZ beads. When both cycle time and specific energy consumption were considered for process optimality, YSZ-CPS bead mixtures performed better than YSZ or CPS alone and the optimal bead mixture was found.