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Title: Investigation of hot-melt extrusion as a means of solubility enhancement for poorly water-soluble drugs
Author: Li, Shu
ISNI:       0000 0004 5370 7835
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2014
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Over the last half a century, hot-melt extrusion (HME) technology has emerging as an extensively studied new strategy of solid dispersion manufacture to achieve enhanced aqueous solubility and hence improved bioavailability for BCS Class II drug. During HME processing, .a number of parameters, such as barrel temperature, screw rotation speed and, screw element configuration, may significantly influence of the properties of the extrudates. However, the determination of those parameters has been often experience oriented rather than rationality directed. In this thesis, Flory-Huggins theory was adapted in combination with melting point depression measurement to address the mixing between the model drug and the chosen excipient as a function of temperature. For each studied binary system, a temperature-composition phase diagram was constructed depicting the direct relationship between interspecies mixing and temperature. Upon construction of such a phase diagram, the mixing between drug and excipient may be split into three zones, namely the soluble, intermediate and, the insoluble zone, by two boundary curves. It was understood that these two boundary curves could be critical in determining HME processing temperatures for binary systems when morphology alterations were concerned. Moreover, a free energy of mixing-composition phase diagram might be generated to reveal spontaneity and extent of mixing as temperature changes. Such information might be used to determine whether increase in mechanical input (kinetics) could significantly compensate the lack of thermodynamic forces during morphology alterations. In a study of amorphous drug dispersions (ADD), results indicated that ADD was only achievable when the HME processing temperature exceeded the solubility curve (boundary between the soluble region and the intermediate region). At low temperatures when spontaneous. interspecies mixing was prevented, increased screw speed would significantly improve amorphization of the model drug. Conversely, when processed at high temperatures and the mixing is thermodynamically favoured, changes in screw speed would not bring significant effects to the solid-state properties of the extrudates. The subsequent drug dissolution studies, however, revealed significantly different ranking of formulations for solubility enhancement due to dissolution mechanism change with test medium pH variations. It was discovered that extreme HME processing parameters, such as particularly high processing temperature or screw speed, could result in uncontrollable extrudate physical properties such as undesired cavity increase, and thus, exhibit unsatisfying dissolution profiles. The adaptation of Flory-Huggins theory and the use of those phase diagrams were also expanded into small molecular material processes. In the latter chapters, an ibuprofen-isonicotinamide cocrystal suspension in a noncomplementary carrier excipient was formulated using single step HME processing for the first time. Upon construction of temperature-composition and free energy-composition phase diagrams, it was established the relationship between solubility of cocrystal components in the chosen carrier excipient and the HME processing temperature. By doing so, appropriate HME processing temperature was selected for the chosen ternary system to achieve increased co crystal yield in the carrier. It was also proved in the last experiment chapter the drastic influence of the incorporation of mixing/kneading elements to the screw configuration on the cocrystal yield within the carrier matrix. Moreover, it was suggested that detailed arrangement of screw geometry ought to vary from case to case based on the cocrystallization mechanism along HME processing. It was emphasized that elements showing distinctively dispersive mixing capacities should be used in the melting zone, whereas those showing distinctively distributed mixing capacities should be employed in a later 'flushing' stage in the cooling zone.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available