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Title:	Foaming of amorphous drug delivery systems prepared by hot melt mixing and extrusion
Author:	Terife, Graciela
View Online:	njit-etd2013-092 (xxxii, 198 pages ~ 10.3 MB pdf)
Department:	Committee for the Interdisciplinary Program in Materials Science and Engineering
Degree:	Doctor of Philosophy
Program:	Materials Science and Engineering
Document Type:	Dissertation
Advisory Committee:	Gogos, Costas G. (Committee co-chair) Xanthos, Marino (Committee co-chair) Simon, Laurent (Committee member) Armenante, Piero M. (Committee member) Faridi, Niloufar (Committee member)
Date:	2013-05
Keywords:	Hot melt extrusion Foaming Foam extrusion HME Amprphous solid solution Release mechanism
Availability:	Unrestricted
Abstract:	Currently there is considerable interest from both academe and pharmaceutical industry in exploring foaming processes and their products in drug delivery applications. However, there is still little knowledge of the impact of the morphology of the foamed structures on the performance of drug products in spite of some publications in this area. Therefore, the main objective of this dissertation is to gain a fundamental understanding of the correlation between foam morphology and performance of amorphous drug delivery systems, which are comprised of an Active Pharmaceutical Ingredient (API) and Polymer excipient. The Hot Melt Extrusion (HME) process is used to compound the following API / polymer binary systems: Indomethacin (INM) with Soluplus® (PVCap-PVAc-PEG); Carbamazepine (CBZ) with PVCap-PVAc-PEG; and INM with Eudragit® EPO. Comprehensive characterization of these binary systems carried out by combining Differential Scanning Calorimetry, Fourier Transform Infrared spectroscopy, X-Ray Diffraction, and Scanning Electron Microscopy, shows that in all HME-prepared and foamed samples the APIs are amorphous and dissolved in the polymer excipients. The most important contributions of this dissertation can be grouped into three areas: (a) an understanding of the mechanisms by which foamed dosage forms can lead to faster API release, as well as the key morphological aspects of the cellular structures to achieve this, (b) an understanding of the correlation between the mechanism controlling the release of an API from an amorphous dosage and the enhancement in its release rate upon foaming, and (c) an understanding of the impact of the morphology of the cellular structures in the milling efficiency of HME products and the dissolution performance of the particles produced. In the first area, foamed amorphous solid solutions with three different morphologies are produced through the batch foaming process. A strong correlation between foam morphology and the enhancement in API release rate is observed. A significant increase in API release rate is achieved by fast disintegration. Through a very broad distribution of wall thicknesses, internal stresses are generated due to different local swelling rates in the sample. In this sense, such foam morphologies act as disintegrant-less disintegrants, speeding up API release and release rates. In the second area, the release controlling mechanisms of INM and CBZ from the amorphous systems are identified by using the Power Law model. Three distinct mechanisms are observed: relaxation controlled, anomalous transport, and diffusion controlled. In all cases, the release rates of the APIs are increased upon foaming. However, in cases where the API release is relaxation-controlled, the foamed structures show to have the strongest impact at the initial stages of its in vitro release. Finally, the Foam Hot Melt Extrusion process is used to produce foamed amorphous solid solutions with two different morphologies. Their performance in terms of milling efficiency and in vitro dissolution behavior is compared to that of the un-foamed extrudates of the same composition. The milling efficiency is increased appreciably through foamed extrudates, and smaller particles with narrower particle size distributions are obtained compared to un-foamed extrudates. Additionally, it is found that the enhancement of the release rate exhibited by milled foamed extrudates is the most significant for the particles produced by milling the lower density foam extrudates.