Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.549131
Title: Analysis of drug polymorphism by diffuse reflectance visible spectroscopy : a novel approach
Author: Ehiwe, Tracy Omosoghogho
Awarding Body: University of Greenwich
Current Institution: University of Greenwich
Date of Award: 2011
Availability of Full Text:
Access from EThOS:
Access from Institution:
Abstract:
The existence of polymorphic forms of drug substances has implications for therapeutic performance, handling and storage. This study investigates the development of a novel approach to surface analysis of drug polymorphs, with the aim of extending the capabilities of this approach to perform real time analysis of polymorphic transformation during pharmaceutical product development. This was achieved here, using diffuse reflectance visible spectroscopy (DRVS) and the colour change which occurs when pH indicator dyes are deposited on the surface. The pH indicators used were phenol red (PR), thymol blue (TB) and methyl red (MR). Two polymorphs each of indomethacin (IMC), carbamazepine (CBZ), caffeine (CFN), sulfanilamide (SFN) and furosemide (FRS) were examined. The interaction of the adsorbed dye with each of the polymorphs showed different behaviour, manifested by different colours. An analysis of the crystal structures and the acid/base properties of the drug molecules provided a rationalisation for the different colours exhibited by the polymorphs‘ surfaces. The least stable form of each polymorphic pair studied showed more extensive interaction with the adsorbed dye molecules. Observed colour reveal underlying differences at a molecular level between the surfaces of pairs of polymorphs. The different colours exhibited by the indomethacin polymorphs were further examined using hygroscopicity studies, contact angle measurements and computer simulation. The contact angles of several liquids with the polymorph surface were measured in order to characterise the nature of the functional groups exposed on the surface of the polymorphs. The surface structure and external morphologies of polymorphs were predicted by molecular modelling using the attachment energy model. The predicted morphology was confirmed by scanning electron micrographs (SEM) and the miller index of the dominant face was confirmed by X-ray powder diffraction (XRD). Results revealed that although the surfaces of both polymorphs are largely hydrophobic, the metastable form- IMC-α has a greater number of polar functional groups on the surface. Further measurements were carried out using DRVS and adsorbed TB to study the kinetics of the solid-state transformation of SFN- to SFN-. The rate of transformation was followed at 128ºC by monitoring the ratio of the two DRVS bands at 454 nm and 604 nm. The kinetic data was analysed using sixteen solid-state kinetic models to obtain the best fit. The thermally induced polymorphic transformation of the SFN-β (particle size of ≥ 450μm) can be best described by the first order kinetic model (R2 = 0.992) with a rate constant, k of 2.43 x 102 s-1. The DRVS instrument used herein is not adapted for in situ studies; however, because of its non-destructive interaction with the sample and rapid data collection time of 5s per spectrum, it does offer considerable potential as a tool for real time monitoring of polymorphic transformation.
Supervisor: Mitchell, John ; Snowden, Martin Sponsor: Engineering and Physical Sciences Research Council (EPSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.549131  DOI: Not available
Keywords: RS Pharmacy and materia medica
Share: