Application of reactive melt extrusion for bioavailability enhancement and modified drug release




Liu, Xu, Ph. D.

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Hot melt extrusion (HME) has been widely applied to prepare amorphous solid dispersions (ASD) to improve the oral bioavailability of BCS Class II and Class IV compounds by increasing their kinetic solubility and dissolution rate. During the HME process, drug, polymer and other excipients are introduced into the barrel at different temperature setting and feed rates. The intermeshing screws mix and melt all materials using heat and an intense mechanical shearing force to achieve distributive and dispersive mixing and excellent homogeneity. The molecular level mixing allows close contact between API and excipients at high frequencies, which provide favorable environment to build drug-excipient intermolecular interactions to improve the physicochemical properties of ASD. Even though there are extensive reports about the pharmaceutical application of HME, most of the studies have been restricted to the manufacture of drug delivery systems where no clearly defined molecular level interaction are produced. Since the extrusion process is a high temperature and aggressive molecular level mixing process, lot of interactions would occur during the extrusion process, such as the ionic interaction, hydrogen bonding, pi-pi interaction, Van der Walls forces and lipophilic-lipophilic interactions. The rational design interactions between drug and excipients during the HME process would provide an inspiring strategy to overcome the drawback of HME, such as the thermal degradation of drug, poor physical stability of drug during the storage time or dissolution process. For ASD development, the polymer carriers play a critical role in stabilizing the drug amorphous state. Polymer selection to prepare the ASDs is largely empirical. There is a need for rational polymer selection, enabling design of stable amorphous solid dispersion. Drug-polymer interactions have been observed to improve the physical stability of ASDs. Supramolecular synthon approach has been applied to design cocrystal with adjusting physicochemical properties. What’s more, supramolecular synthon approach has been exploited to design ASD with exceptional physical stability. Based on all those non-covalent interactions, it is possible to achieve the in-situ modification of solid forms of active pharmaceutical ingredients by mechanochemistry using extrusion process, without changing the pharmacology of the API. The major goal of this research is to explore rational design interaction between drug and excipients during the HME process to prepare salt, polyelectronic complexes, nanocomposites, cocrystal and coamorphous to improve the oral bioavailability of poorly water-soluble drugs and adjusting drug release rate. In Chapter 1, we reviewed the most commonly used methods for characterization of ASDs both in solid state or in aqueous media. The advantage and disadvantage of each method is briefly summarized. All methods are divided into three different categories: microscopic and surface analysis methods, thermal analysis methods and spectroscopic methods. The latest characterization techniques are also introduced. Last, we discuss how these methods are applied at different stages in the ASDs product development life cycle. In Chapter 2, we investigate the reaction between naproxen and meglumine at elevated temperature with different molar ratio and study the impact of this reaction on the physical stabilities and in vitro drug-release properties of melt-extrudated naproxen amorphous solid dispersion. In Chapter 3, we use reactive melt extrusion to prepare sustained release lidocaine polyelectrolyte complex. In this study, the influence of the drug form (freebase vs. hydrochloride salt) on lidocaine-Eudragit L100-55 interactions, physical stability, and dissolution properties of extrudates was investigated. In Chapter 4, we prepare exfoliated montmorillonite-Eudragit RS nanocomposites using reactive melt extrusion and investigate the influence of clay loading, clay types on clay-polymer interactions and drug release properties. The clays are used as the filler material with Eudragit RS at different concentration and theophylline was the model compound. The resulting structure of the nanocomposites were characterized using TEM and XRPD. The hygroscopicity of the nanocomposites was investigated using DVS. The effect of the interfacial interaction between the polymer and the clay sheet, the clay loading as well as the clay type on the drug release behavior were further studied by the dissolution testing.


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