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dc.contributor.advisorRades, Thomas
dc.contributor.advisorGordon, Keith
dc.contributor.advisorKrauel-Goellner, Karen
dc.contributor.authorZimper, Ulrike
dc.identifier.citationZimper, U. (2011). Milling Behaviour of Drugs (Thesis, Doctor of Philosophy). University of Otago. Retrieved from
dc.description.abstractMilling is a common pharmaceutical unit operation, which provides two possible pathways to enhance the dissolution rate of poorly water soluble drugs: particle size reduction and solid state form transformation. This thesis is investigating the effect of milling on the solid-state properties and dissolution rate of different BCS-class II compounds. Milling was conducted on an oscillatory ball mill and a media (bead) mill. For particle size reduction, any process induced transformation (PIT), i.e., solid-state alteration during milling needs to be avoided in order to ensure the final product quality. However, the milling conditions applied in industrial settings do not necessarily lead to distinct singular solid-state forms (like defined crystalline polymorphs or completely amorphous forms) of an active pharmaceutical ingredient. Hence, the challenge of this thesis lay in the determination of various degrees of process-induced disorder, which was hypothesized to be generated during milling. X-ray powder diffraction, differential scanning calorimetry and Raman spectroscopy were the analytical methods that were compared with respect to the detection and quantification of solid-state modifications and process induced disorder. Complementarity as well as advantages and disadvantages of each method are investigated and discussed in this thesis. Process induced disorder and particle size are the two opposing responses in a milling operation. A central composite face centered design was utilized to optimize a dry ball milling operation with regard to these responses. The dissolution rate of the optimized formulation was investigated with regard to the impact of process induced disorder and particle size on dissolution. It was found that process induced disorder was negligible with respect to the dissolution rate and the primary particle size could not be translated into a dissolution rate advantage due to particle agglomeration. Since particle agglomeration of small primary particles to larger secondary particles was found to be a hindrance in dry milling processes, wet milling as an alternative milling operation was explored with regard to its effect on process induced disorder and dissolution rate enhancement for the BCS-class II model compound BIX. A PLS model was developed which allowed for the semi-quantitative determination of process-induced disorder in a media milling process. Furthermore, a nano-crystalline drug formulation of BIX was compared to an amorphous drug formulation with regard to dissolution rate improvement. The amorphous drug formulation failed to enhance the dissolution rate of BIX due to recrystallisation upon dissolution. Overall, if the objective is to enhance the dissolution performance of a poorly water soluble drug whilst limiting the introduction of crystalline disorder during processing, nano-crystal drug formulation by wet media milling proved to be a superior formulation approach over dry ball milling and amorphous formulation for the model drug investigated in this thesis.en_NZ
dc.publisherUniversity of Otago
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dc.subjectSolid Stateen_NZ
dc.subjectMultivariate Analysis (MA)en_NZ
dc.subjectDesign of Experiments (DoE)en_NZ
dc.subjectProcess Induced Transformation (PIT)en_NZ
dc.subjectDissolution Rateen_NZ
dc.titleMilling Behaviour of Drugsen_NZ
dc.typeThesis of Pharmacyen_NZ of Philosophyen_NZ of Otago Theses
otago.openaccessAbstract Only
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