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Infrared (IR) spectroscopy
IR spectra originate from the absorption of a photon between two vibrational energy levels. In general, a vibrational mode is IR-active when the dipole moment, μ, associated with the mode is non-zero. From quantum mechanics it is shown that molecular vibrational energy levels are quantised and that the dipole moment of an associated vibration will couple with the electric field of the IR radiation, IR, only when the associated energy of this IR radiation matches that of a specific vibrational energy level of the molecule, allowing the absorption and emission of IR photons by vibrational energy levels in the molecule’s electronic ground state.
Raman spectroscopy
Raman spectroscopy is a scattering technique during which a sample is irradiated with a single wavelength source (i.e. a laser) and electronic polarisation is induced in the dipole associated with a vibrational mode. Three scattering processes can occur when the sample is irradiated: Rayleigh, Stokes and anti-Stokes scattering. Rayleigh scattering occurs when the frequency of the scattered radiation equals that of the incoming radiation [26]. When the scattered radiation’s frequency differs from that of the incident radiation, Stokes/anti-Stokes scattering occurs and it is the frequency difference between the incident and scattered radiation that is of interest to the spectroscopist.
Molecular modelling
Molecular modelling is used to assist with and/or confirm many aspects of experimental chemistry. If the theory is an acceptable description of the system of interest, a wealth of information can be obtained theoretically, which would usually be very time-consuming to obtain experimentally. In the case of HEDP, the vibrational spectra are complex and many ambiguous, overlapping bands are observed, making empirical assignment very difficult. Calculation of the theoretical spectra can therefore be used to confidently identify and confirm bands that can be associated with chemical or conformational changes, as well as the associated intra/intermolecular interactions.
The theoretical method
Two main methods are used in molecular modelling: molecular mechanics (MM), which is based on the laws of classical physics, and the electronic structure method, which is based on quantum mechanics [27]. The latter can be divided into semi-empirical, ab initio and density functional theory (DFT); the most widely used of these is the DFT method which takes the effects of electron correlation into account [27]. The DFT method is very similar to the ab initio Hartree-Fock (HF) method, but here the electron is assumed to interact with an ‘averaged electron density’.
Aim
The general use of bisphosphonates in bone degenerative diseases has been outlined, as well as the techniques and methods employed in this thesis. Very little is known about the interactions of bisphosphonates with bone on a fundamental, molecular as indicated by an analysis of available literature.
Therefore the need exists for a more fundamental study of these compounds. HEDP is the oldest known, benchmark and chemically simplest bisphosphonate and would therefore be the most logical point to start such an investigation using hydroxyapatite as a simplified model for bone.
In all fundamental studies the validation of both theoretical and experimental methods are important. Therefore many relevant spectroscopic techniques as earlier described were used and the experimental data rationalised by theoretical calculations / methods.
It is therefore the aim of this thesis to investigate the interaction of HEDP with hydroxyapatite as a model of bone on a fundamental level using these various techniques for future extension and methodology development to study other bisphosphonates and solution/solid interaction environments more relevant to cancerous environments in the human body.
1. Introduction
1.1 Bisphosphonates
1.2 Radiopharmaceutical uses of bisphosphonates
1.3 HEDP properties
1.4 Hydroxyapatite as a model of bone
1.5 Spectroscopic methods
1.6 Molecular modelling
1.7 Aim
1.8 References
2. Experimental
2.1 Introduction
2.2 Chemicals
2.3 NMR spectroscopy
2.4 Thermal gravimetric analysis
2.5 X-ray diffraction methods
2.6 Rietveld refinement
2.7 Molecular modelling
2.8 Vibrational spectroscopy
2.9 Multivariate curve resolution (MCR)
2.10 References
3. Results and Discussion
3.1 Introduction
3.2 NMR spectroscopy
3.3 Thermal gravimetric analysis
3.4 X-ray diffraction methods
3.5 Vibrational spectroscopy and molecular modelling
3.6 Multivariate curve resolution
3.7 Conclusions
3.8 References
4. Interactions of HEDP with HA
4.1 Introduction
4.2 The interaction of HEDP with various calcium phosphates
4.3 Conclusions
4.4 References
5. Conclusions
5.1 Summary
5.2 NMR spectroscopy
5.3 X-ray diffraction methods
5.4 Vibrational spectroscopy
5.5 Modelling techniques
5.6 The holistic approach
5.7 Future work
APPENDIX
