This study has presented a series of novel approaches for the identification, quantification and prediction of phase separation in HME formulations. Supersaturation of drug in the polymer caused the phase separation of the aged felodipine-Eudragit E PO formulations.
We have demonstrated that the novel combined approach allows site-specific characterisation of the extruded systems and that drug distribution may be uneven across the extrudates, with concomitant implications for understanding stability and drug release behaviour.
This study proposes use of the phase separation of immiscible polymer blends as a formulation approach to improve the stabilization and solubilization of amorphous molecular dispersions of poorly soluble drugs. This approach uses the phase separation and different drug solubilization properties of the two immiscible polymers in the blend to optimize drug loading and stabilization. The model system tested in this study is a EUDRAGIT E PO-PVP-VA 50/50 (w/w) blend loaded with felodipine via hot melt extrusion. The phase separation behavior of the polymer blend and drug loaded polymer blend formulations were characterized using a range of thermal (MTDSC), spectroscopic (ATR-FTIR), and imaging (AFM and thermal transition mapping) techniques. The polymer blend formulations demonstrated superior performance in drug release as well as stabilization against stressed temperature, stressed humidity, and mechanical milling in comparison to the drug-polymer binary systems. This is attributed to the configuration of the phase separated microstructure of the polymer blend formulations where the hydrophilic polymer domains host high concentrations of molecularly dispersed drug which are protected from moisture induced recrystallization on aging by the hydrophobic polymer domains. Additionally drug incorporation as a molecular dispersion in different polymer phases reduces the drug recrystallization tendency on aging under high temperatures and during milling.
The solubility of drugs in polymer matrixes has been recognized as one of the key factors governing the physical stability of solid dispersions. This study has explored the implications of drug solubility on the destabilization that occurs on milling, which is often used as an additional process for hot melt extruded (HME) solid dispersions. The theoretical drug solubility in the polymer was first predicted using various theoretical and experimental approaches. The destabilization effects of high-energy mechanical milling on the solid dispersions with drug loadings below and above the predicted solubility were then investigated using a range of thermal, microscopic, and spectroscopic techniques. Four model drug-polymer combinations were studied. The HME formulations with drug loading below the predicted solid solubility (undersaturated and true molecular dispersion) showed good stability against milling. In contrast, milling destabilized supersaturated HME dispersions via increasing molecular mobility and creating phase-separated, amorphous, drug-rich domains. However, these additional amorphous drug-rich domains created by milling show good stability under ambient conditions, though crystallization can be accelerated by additional heating. These results highlighted that the processing method used to prepare the solid dispersions may play a role in facilitating the stabilization of amorphous drug in supersaturated solid dispersions. The degree of supersaturation of the drug in the polymer showed significant impact on the destabilization behavior of milling on solid dispersions. An improved understanding of the destabilization behavior of solid dispersions upon milling can provide new insights into the processing related apparent solubility of drugs in polymers.
The stability of the amorphous drug-rich domains appears to be governed by the physical stabilities of the amorphous drugs. The more commonly used indicators such as Tg, fragility of the amorphous drug and the theoretically predicted drug-polymer solubility showed less influence on the bulk and surface stabilities of the extrudates in comparison to the molecular mobility of the amorphous drug.
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