Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.687794
Title: Study of the photodegradation and photostability of anti-cancer drugs in different media towards the development of both new actinometers and liquid formulations
Author: Lee, Lok Yan
ISNI:       0000 0004 5915 4282
Awarding Body: De Montfort University
Current Institution: De Montfort University
Date of Award: 2016
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Abstract:
This study aims at tackling some of the problems often encountered in photostability testing and liquid formulation development. Three anti-cancer drugs will be employed as models; Dacarbazine (DBZ) has well established photostability issues, Axitinib (AXI) and Sunitinib (SUT) are two new drugs only commercially available in solid dosage forms. In ethanol, the photokinetics of these drugs were well described by the newly proposed Φ-order kinetic mathematical model. This has confirmed the photoreversible character of AXI and SUT’s and unimolecular photoreaction of DBZ’s photodegradations. Also, the Φ-order kinetics is proven to describe them better than the usually used classic thermal reaction orders. In aqueous solution, the drugs were found to undergo thermal and photochemical complex degradations, involving at least 3 photoproducts. A new photokinetic approach has been proposed in this work to solving and unravelling the attributes of such complex mechanisms. For the first time, the quantum yields (QY) of the three drugs were determined and found to increase with irradiation wavelength. SUT’s QY were comparable in ethanol and water (QY460 = 0.02), DBZ was found to be more photoefficient in water (QY330 = 0.04 and 0.1, respectively) and AXI in water (QY330 = 0.06 and 0.03). Φ-order kinetics’ potential for the development of reliable actinometers of the three drugs, without prior knowledge of unknown reaction parameters, has also been established. A general equation to describe the isotherm of a (Gn:Hm) guest-host multicomponent complex was proposed in this work to palliate the lack of a strategy for characterising nanosponge-drug complexes. It provides information on both stiochiometry and association constant of the complex. The results indicate that hydrophobic AXI forms a 1:0.8 complex, indicating the possibility of multiple association sites and/or different types of binding. The newly developed AXI/nanosponge liquid formulation has significantly increased solubility (5000-fold) and thermal stability. Furthermore, the photostability of DBZ and SUT were considerably improved by using a strategy based on light-absorption competitors. Their initial velocities reduced from 10 and 3 s-1 (respectively) to 1 and 0.13 s-1. The successful application of these methods to the model anti-cancer drugs has set out new approaches that might be found useful for future treatments of photodegradation data, development of drug-actinometers and liquid formulations of drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.687794  DOI: Not available
Keywords: photostability ; photodegradation ; anti-cancer ; dacarbazine ; axitinib ; sunitinib ; photostability ; stabilization ; formulation ; F-order ; modelling ; kinetic ; photokinetic ; degradation ; cyclodextrin ; nanosponge ; actinometer ; characterisation ; complexation ; complex ; quantum yields ; photoreversible ; isomers ; isotherm ; spectroscopic ; fluorimetry ; stiochiometry ; association constant ; binding constant
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