Microstructure of an Immiscible Polymer Blend and Its Stabilization Effect on Amorphous Solid Dispersions

Abstract

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.

Characterization of Heterogeneity and Spatial Distribution of Phases in Complex Solid Dispersions by Thermal Analysis by Structural Characterization and X-ray Micro Computed Tomography

“…The dissolution results indicate that the phase-separated carrier systems that contain no crystalline drug can significantly improve drug release. Even with only one side of the intact patches in contact with the dissolution media, this dissolution enhancement is comparable with other binary solid dispersion systems reported in the literature where milled extrusion powders with much higher total surface area for dissolution were used (9).

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“…This is largely a result of a lack of understanding regarding the mechanisms of the formation and ability to control of the progression of phase separation. More recently however, intentionally forming phase separated solid dispersions to improve stability or modulate the drug release profile has been proposed (9–11). From the literature, the most commonly observed phase separation behavior in solid dispersions is the separation of the incorporated drug from the carrier polymer and excipient materials (if more than one carrier material was used) (9,10) as either amorphous or crystalline domains (12–14).…”

“…Micro/nano thermal analysis can pin-point the different phases present in the dispersion by identifying the differences in their thermal transition temperatures using heated AFM tips. The recent development of local nano-thermal analysis into an imaging method, transition temperature microscopy (TTM), has demonstrated the capacity of allowing the mapping of phase separation in some dispersion formulations (9,19). However, the disadvantage of micro/nano thermal analysis and TTM is that the measurements are often time consuming.…”

The Need for Restructuring the Disordered Science of Amorphous Drug Formulations

“…relatively lower temperature and mechanical activity) compared to temperature-based and mechanical-based methods make them more flexible in terms of selecting the best compound and excipient, as long as both components are miscible and soluble in the solvent system used. However, more stringent criteria are required for temperature-based methods, including criteria for the T g and the T m of both the compound and the excipient, the viscosity of the excipient, the miscibility of the components, the extrudability of the mixture, and the potential degradation of the compound on exposure to high temperature during the process (74,76,103,109,129,138,150,155,175). These could limit the applicability and use of temperature-based methods in the preparation and study of amorphous formulations.

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An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing

“…Solid dispersions are widely used formulations for improving the dissolution of poorly water-soluble drugs [14,15]. Molecular dispersions in which the crystalline drug is dispersed in the polymeric matrices on a molecular scale have been recognized as being highly effective for improving the dissolution and subsequent bioavailability of many poorly soluble drugs [16,17]. This study used a BCS class II drug [18], felodipine, as a model poorly soluble drug to develop FDM 3D printable blends made of pharmaceutically approved excipients.…”