Application of Melt Extrusion in the Development of a Physically and Chemically Stable High-Energy Amorphous Solid Dispersion of a Poorly Water-Soluble Drug

Abstract

Formulation of active pharmaceutical ingredients (API) in high-energy amorphous forms is a common strategy to enhance solubility, dissolution rate and, consequently, oral bioavailability of poorly water-soluble drugs. Amorphous APIs are, however, susceptible to recrystallization and, therefore, there is a need to physically stabilize them as solid dispersions in polymeric carriers. Hot melt extrusion has in recent years gained wide acceptance as a method of choice for the preparation of solid dispersions. There is a potential that the API, the polymer or both may degrade if excessively high temperature is needed in the melt extrusion process, especially when the melting point of the API is high. This report details a novel method where the API was first converted to an amorphous form by solvent evaporation and then melt-extruded with a suitable polymer at a drug load of at least 20% w/w. By this means, melt extrusion could be performed much below the melting temperature of the drug substance. Since the glass transition temperature of the amorphous drug was lower than that of the polymer used, the drug substance itself served as the plasticizer for the polymer. The addition of surfactants in the matrix enhanced dispersion and subsequent dissolution of the drug in aqueous media. The amorphous melt extrusion formulations showed higher bioavailability than formulations containing the crystalline API. There was no conversion of amorphous solid to its crystalline form during accelerated stability testing of dosage forms.

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

“…The most commonly used traditional plasticizers are triacetin (48), citrate ester (41,49), vitamin E D-alpha tocopheryl PEG 1000 succinate (TPGS) (50), surfactants (51), and lowmolecular-weight polyethylene glycols (31). Non-traditional plasticizers are included in formulations to serve other critical functions and are often low-molecular-weight materials such as the active substance itself (52)(53)(54)(55). Special plasticizers are low-molecular-weight materials, which also act as plasticizers for polymeric carriers depending on their physical state.…”

Investigation of Thermal and Viscoelastic Properties of Polymers Relevant to Hot Melt Extrusion, IV: Affinisol™ HPMC HME Polymers

“…However, various issues related to formulation, manufacturing, and physical stability of solid dispersions have for a long time hindered its widespread application in drug product development (7). The situation has changed greatly in the past decade because of the introduction of hot melt extrusion (HME) for the preparation of solid dispersion (8)(9)(10)(11). In HME, the drug is solubilized in a polymeric matrix by processing blends of drug, polymer, and any other excipients at high temperatures in a hot melt extruder (9).…”

The Use of Binary Polymeric Networks in Stabilizing Polyethylene Oxide Solid Dispersions

“…toxicity, safety hazards and solvent residuals make melting the method of choice despite of the potential problem of thermal degradation of drugs and carriers. Over the last decade, hot-melt extrusion (HME) has gathered renewed interest, particularly with regard to production of solid dispersions (Albers et al, 2009;Lakshman et al, 2008;Miller et al, 2008, Tian et al, 2014.…”

“…toxicity, safety hazards and solvent residuals make melting the method of choice despite of the potential problem of thermal degradation of drugs and carriers. Over the last decade, hot-melt extrusion (HME) has gathered renewed interest, particularly with regard to production of solid dispersions (Albers et al, 2009;Lakshman et al, 2008;Miller et al, 2008, Tian et al, 2014.Polyethylene oxide (PEO) is a semicrystalline non-ionic thermoplastic polymer exhibiting a low melting point, rapid solidification rate and low toxicity making it ideal for HME and formation of amorphous solid dispersion (Zhang and McGinity, 1999).Due to their hydrophilic character and ability to form solid dispersions, lower molecular weight PEOs have been widely used as carriers to enhance the solubility/dissolution properties of poorly soluble drugs (Li et al, 2006;Ozeki et al, 1997;Schachter et al, 2004). Melting of PEO followed by solidification upon cooling may decrease PEO crystallinity, and hence increase the amorphous PEO fraction (Prodduturi et al, 2005).…”