Hot melt extrusion of heat-sensitive and high melting point drug: Inhibit the recrystallization of the prepared amorphous drug during extrusion to improve the bioavailability.

Using tadalafil (TD) as a representative of heat-sensitive drug with high melting point and strong crystallization tendency, we observed that recrystallization of the prepared amorphous materials during extrusion can result in failure of amorphous solid dispersion (ASD) extrusion. Such recrystallization process of amorphous TD during reheating process was investigated systematically. Our results show that spray-dried amorphous TD sample is more prone to recrystallize (occurs from 150 °C) in comparison to the melt-quenched amorphous TD sample (recrystallizes from 190 °C). Poor stability of the spray-dried TD sample is likely due to an excessive amount of available surface area. Co-extruding Soluplus with spray-dried amorphous TD at 160 °C could yield ASD at 10% drug loading and crystalline solid dispersion above 20% drug loading. The method that spray drying 20% TD with 80% Soluplus and then extruding the spray-dried sample can obtain ASD at 20% drug loading at 160 °C, 142 °C lower than the melting point of TD (302 °C). More importantly, the samples prepared by such strategy exhibited a substantially improved bioavailability compared to the samples that were prepared by either spray-dried or hot-melt extruded processes.

Enhancement of the apparent solubility and bioavailability of Tadalafil nanoparticles via antisolvent precipitation.

The ability to increase the bioavailability and dissolution of poorly soluble hydrophobic drugs has been a major challenge for pharmaceutical development. This study shows that the dissolution rate, apparent solubility and oral bioavailability of tadalafil (Td) can be improved by nano-sized amorphous particles prepared by using antisolvent precipitation. Acetone and an acetone-water solution (v:v, 9:1) were selected as solvents, with deionized water as the antisolvent. The antisolvent precipitation process was conducted at a constant drug concentration of 10 mg/ml, at temperatures of 5, 10 and 15 °C and at volume ratios of antisolvent to solvent (AS/S) of 5, 8 and 10. Solid dispersion was achieved by dissolving the polymer in the antisolvent prior to the precipitation and by spray drying the suspension after the antisolvent precipitation process. The selected polymers were HPMC, VA64, and PVPK30 at concentrations of 33, 100 and 300 mg per 100 ml of water (equivalent to weight ratios of drug-to-polymer of 1:3, 1:1 and 3:1, respectively). The solid dispersions were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FT-IR). The improvements in the dissolution rate, equilibrium solubility, apparent solubility and bioavailability were tested and compared with unprocessed Td. Td particles in the suspension (before spray drying) were 200 nm, and the obtained Td solid dispersion had a size of approximately 5-10 µm. The XRPD, DSC and FT-IR analyses confirmed that the prepared Td particles in the solid dispersions were amorphous. The solid dispersion obtained using the optimized process conditions exhibited 8.5 times faster dissolution rates in the first minute of dissolution, 22 times greater apparent solubility at 10 min and a 3.67-fold increase in oral bioavailability than the as-received Td. The present work demonstrated that low temperature antisolvent precipitation technique has excellent potential to prepare nano-sized amorphous particles with a faster release and a higher bioavailability.