Hot Melt Extrusion for Amorphous Solid Dispersions: Temperature and Moisture Activated Drug–Polymer Interactions for Enhanced Stability

Abstract

Hot melt extrudates (HMEs) of indomethacin (IND) with Eudragit EPO and Kollidon VA 64 and those of itraconazole (ITZ) with HPMCAS-LF and Kollidon VA 64 were manufactured using a Leistritz twin screw extruder. The milled HMEs were stored at controlled temperature and humidity conditions. The samples were collected after specified time periods for 3 months. The stability of amorphous HMEs was assessed using moisture analysis, thermal evaluation, powder X-ray diffraction, FTIR, HPLC, and dissolution study. In general, the moisture content increased with time, temperature, and humidity levels. Amorphous ITZ was physically unstable at very high temperature and humidity levels, and its recrystallization was detected in the HMEs manufactured using Kollidon VA 64. Although physical stability of IND was better sustained by both Eudragit EPO and Kollidon VA 64, chemical degradation of the drug was identified in the stability samples of HMEs with Eudragit EPO stored at 50 °C. The dissolution rates and the supersaturation levels were significantly decreased for the stability samples in which crystallization was detected. Interestingly, the supersaturation was improved for the stability samples of IND:Eudragit EPO and ITZ:HPMCAS-LF, in which no physical or chemical instability was observed. This enhancement in supersaturation was attributed to the temperature and moisture activated electrostatic interactions between the drugs and their counterionic polymers.

Improved dissolution and bioavailability of silymarin delivered by a solid dispersion prepared using supercritical fluids

“…However, more drug loss was observed in SM-SD-SE than in SM-SD-SEDS. This may reflect increased molecular motion within SM-SD-SE, recrystallization of the amorphous drug, and the associated chemical degradation [21,22]. Furthermore, the XRD result for SM-SD-SEDS was similar on day 0 and at 6 months ( Fig.…”

Support Tools in Formulation Development for Poorly Soluble Drugs

“…Therefore, the stability of amorphous drugs has been the subject of many studies. [34][35][36][37][38][39] If the amorphous stability of an API could be predicted early on in the formulation development, it would be possible to conclude if amorphization were a viable route for an API. Nurzynska et al 40 recently developed a predictive model of the amorphous stability of neutral poorly soluble drugs.…”

Bioavailability Improvement Strategies for Poorly Water-Soluble Drugs Based on the Supersaturation Mechanism: An Update

“…For example, in the Eudragit L system, Carbopol1 974P can be used as a stabilizer (66). Other results have suggested that the Eudragit has the fastest in vitro dissolution pattern because of its high degree of supersaturation among the three PIs (PEG6000, PVP K30 and Eudragit) (67).…”