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Title: Innovative approaches towards understanding the dissolution and growth of active pharmaceutical ingredients
Author: Maddar, Faduma
ISNI:       0000 0004 7227 5070
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2017
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Studies of the kinetics and mechanisms of the dissolution and growth of crystals and other solids are beneficial in many areas of science. In pharmaceutical science, dissolution testing is a key quality control procedure used to determine the rate at which an active pharmaceutical ingredient (API) is released and is thus available for absorption in the gastro-intestinal tract. However, the general processes governing the dissolution and growth of crystals are poorly understood despite many years of study. This thesis focuses on the implementation of various microscopy and electrochemical techniques as a novel approach to further understand the dissolution and growth of API crystals and amorphous solids. The motive of the first part of the thesis, was the use of atomic force microscopy (AFM) to obtain new insight into API dissolution and growth from both the crystalline form and amorphous solid state. Studies of the crystalline API, bicalutamide have focused on measuring the 3D morphological changes of individual microcrystals in aqueous solution, in real time, from which the intrinsic dissolution rates of each crystal surface exposed to solution have been extracted. In addition, with finite element method (FEM) modelling, interfacial concentrations around the dissolving crystal have been obtained, allowing the elucidation of the kinetic regime of the overall dissolution reaction. A major conclusion of this work is that the dissolution kinetics accelerate significantly during the process, due to changes in nanoscale features on the surface. AFM was then used to examine targeted regions of dissolving amorphous solid dispersions (ASDs), comprising of felodipine API and the water-soluble polymer copovidone, in aqueous solution, together with a localized electrochemical-droplet (flux measuring) technique and Raman spectroscopy. This multi-microscopy approach allowed real-time information about initial API release rates, and changes in solid-state composition and morphology during dissolution. This thesis then transitions to the study of nanocrystallization of APIs using nanopipettes under electrochemical control in a nanoscale anti-solvent configuration using bicalutamide, as an example system. A key feature of the technique is that a bias between an electrode in the nanopipette, and one in bulk solution, can be used to control the supersaturation level at the end of the nanopipette and the current-time response detects nucleation and growth events. Using Raman microscopy the formation of the least stable crystal polymorph of Form II was demonstrated. To highlight the generality of nanopipette-based electrochemical techniques, a final results chapter reports the use of scanning electrochemical cell microscopy (SECCM) to study the electro-oxidation of nicotinamide adenine dinucleotide (NADH), on various carbon electrodes, showing how active surface sites are readily identified and quantified.
Supervisor: Not available Sponsor: AstraZeneca ; University of Warwick ; Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry