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Title: Development of new approaches for assessing miscibility and the solid state structure of olanzapine dispersions in polymeric carriers
Author: Askin, Sean L.
ISNI:       0000 0004 7659 7640
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Drug-polymer dispersions are a well-established formulation strategy, with many commercial products utilising this technology to either increase bioavailability of poorly water soluble compounds or produce controlled release systems. The main limitation of these formulations is their long-term physical stability since these systems are often unstable supersaturated molecular dispersions. This instability can lead to recrystallisation of the drug, potentially affecting the dissolution performance. In this work, new analytical methods were applied to provide understanding into the crystallisation behaviour of a model drug, olanzapine, in several polymer dispersions. The intention was to develop new insights into the physical drivers for crystallisation, the means by which it can be detected and predicted, and the possibility of utilising this knowledge to manipulate the crystal form. Olanzapine-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were initially produced. The physical stability of this system was assessed through drug-polymer solubility measurements. Several de-mixing approaches were compared in which supersaturated dispersions were recrystallised to achieve the equilibrium solubility level of the drug in the polymer phase. During this work a quasi-isothermal modulated temperature differential scanning calorimetry (QiMTDSC) protocol was developed and applied to study crystallisation in these systems. Drug-polymer solubility was successfully measured using this approach and drug crystallisation could also be monitored, allowing investigation of the conditions under which the solubility equilibrium could be achieved. Olanzapine is a polymorphic molecule and the study of its recrystallisation in PLGA dispersions highlighted that standard techniques could not determine which form was crystallising. Thus, a new simultaneous differential scanning calorimetry-powder X-ray diffraction (DSC-PXRD) method was applied to characterise olanzapine crystallisation in several polymer dispersions. Interestingly, drug crystallisation was influenced by the different polymers present. A new polymorph, olanzapine form IV, was discovered which indicated that this crystallisation approach can be used as an alternative method for polymorph screening. A process was developed to extract form IV crystals from the polymer matrix, providing the proof-of-concept that this approach can be used to generate and isolate new polymorphic forms.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available