| Summary: | Hot-melt extrusion (HME) is one of the most widely used technologies in the plastic, rubber and food industries and it has also been extensively explored and used in academia and the pharmaceutical industry over the last decade. This project aims to investigate the efficiency of hydrophilic polymers to enhance the dissolution rate of poorly water-soluble APIs processed by HME. Indomethacin (INM) and famotidine (FMT) were selected as model active substances while polyvinyl caprolactam graft copolymer, Soluplus® (SOL) and vinylpyrrolidone-vinyl acetate copolymer grades Kollidon® VA64 (VA64) and Plasdone® S630 (S630) were used as hydrophilic polymeric carriers. For the purpose of the study, all drug-polymer binary blends at various ratios were processed by a Randcastle single screw extruder. The physico-chemical properties and the morphology of the extrudates were evaluated via x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). INM and FMT exhibited strong plasticization effects at specific concentrations and were found to be molecularly dispersed within the polymer blends. The in vitro dissolution studies showed increased INM/FMT release rates for all formulations compared to that of pure APIs alone. Ibuprofen was also embedded in a methacrylate copolymer (Eudragit® EPO) matrix to produce solid dispersions by hot-melt extrusion processing. The obtained granules were incorporated into orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and cross-linked polyvinylpyrrolidone while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, and friability and dissolution profiles were further evaluated and compared with commercially available Nurofen® Meltlet ODTs. In vitro dissolution of the extruded ODTs showed rapid release of ibuprofen compared to that of Nurofen® Meltlets. The in vitro and in vivo evaluation of the masking efficiency of hot melt extruded paracetamol (PMOL) formulations was examined. Extruded granules containing high PMOL loadings in Eudragit EPO® (EPO) or Kollidon® VA64 (VA64) were prepared by HME. Similarly propranolol HCl (PRP), diphenhydramine HCl (DPD), cetirizine HCl (CTZ) and verapamil HCl (VRP) were used as model cationic active substances while pH sensitive anionic methacrylic acid based methyl methacrylate coplolymers Eudragit® L100 (L100) and ethyl acrylate copolymer Eudragit® L100-55 (Acryl-EZE®) (L100-55) were used as polymeric carriers in order to produce taste masked extruded formulations determining drug-polymers intermolecular interactions. The taste masking effect of the processed formulation was evaluated in vivo by a panel of six healthy human volunteers. In addition, in vitro evaluation was carried out by an Astree e-tongue (Alpha MOS) equipped with seven sensors and Taste Sensing System TS5000Z (INSENT), respectively. The taste and sensory evaluation in human volunteers demonstrated that the formulation masked the bitter taste of the APIs and improved tablet palatability. In addition to that the taste sensing technology demonstrated taste improvement for all polymers by correlating the data obtained for the placebo polymers and the pure APIs alone. The e-tongue results were in good agreement with the in vivo evaluation. Molecular modelling (Gaussian 09) predicted the existence of two possible H-bonding types while Fourier Transform Infra-Red (FT-IR) and NMR studies confirmed drug-polymer interactions between the functional groups of both components (cationic drugs–anionic polymers). Furthermore, the intermolecular interactions evaluated by Flory-Huggins interaction parameters theory and X-ray photoelectron spectroscopy (XPS) showed stronger interactions between drug-polymer in L100 systems compared to that of L100-55 systems. The mechanism of the intermolecular interactions derived from this research showed the presence of H bonding between the amine group of the active substances and the carboxylic groups in the polymer. Hydrocortisone (HCS) was also embedded and extruded with ethyl cellulose N10 (EC N10) or ethyl cellulose Premium 7 (EC P7) in order to develop sustained release tablets processed by HME. The compressed tablets were subsequently coated with an enteric coating polymer, Eudragit® S100 (15-20%), which showed sustained release over 12 hrs with a lag time of 2 hrs. Further analysis of the release mechanism of HCS from tablets was performed by implementing five different kinetic release models which confirmed that the release of HCS from both coated and uncoated tablets followed a first order kinetic model.
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