Pharmaceutical and Biomedical Applications of Spectroscopy in the Photon Migration Regime
Sammanfattning: The present thesis is devoted to two different matters: One part is the development of a novel optical technique for characterisation of solid pharmaceutical materials. The other part being the continued development of photon time-of-flight spectroscopy, as well as exploration of new application areas of this method. These two optical techniques are conceptually and technically very different, but they are both designed for analysis of highly scattering materials (that is, materials in which light frequently changes its direction of propagation). In this thesis, the techniques are applied for chemical analysis and analysis of structural properties of for example pharmaceutical tablets, human prostate tissue, and female breast tissue. The new optical method for analysis of structure in pharmaceutical solids enables non-destructive measurement of properties such as porosity. Structural properties are measured indirectly through measurements of the very weak, but detectable, light absorption by the oxygen molecules that are dispersed within the sample. The total absorption by oxygen is not only determined by sample porosity, but is also strongly influenced by scattering properties. A moderately compressed tablet of 3 to 4 mm thickness can, due to long optical pathlengths in transmission, give rise to absorptions corresponding to tens of millimeters through ambient air. The sensitivity to sample structure makes this technique highly interesting in, for example, process monitoring. It can also be used in predicting important pharmaceutical parameters such as drug release and dissolution. The technique is based on ultrasensitive, high-resolution diode laser spectroscopy - a technique commonly used for gas analysis in, for example, atmospheric sciences and pollution monitoring. However, the detection of gases within solids and scattering materials is accompanied by several aggravating circumstances, setting special requirements on measurement procedure and instrumentation. While conventional use of the technology involves well defined beamlines and gas cells, this thesis deals with detection of weak intensities of diffuse light and devastating optical interference. The other part of this thesis is concerned with pharmaceutical and medical applications of ultrashort (picosecond) laser pulses for analysis of chemical composition and material structure of highly scattering samples. The technique is referred to as time-of-flight spectroscopy or time-resolved spectroscopy. A short pulse of light injected into a scattering material will, upon detection at some distance from the injection location, appear broadened in time due to that different photons have travelled different distances at the same speed. The measurement of the temporal distribution of the detected light (i.e. the photon time-of-flight distribution) allows circumventing the difficulties encountered in conventional absorption spectroscopy. The time-of-flight distribution is a direct measure of the previously unknown optical pathlength, and the shape of the distribution can be used for quantification of both absorption and scattering. The most important contributions of the present thesis, related to this technique, include the development of sophisticated modelling of light propagation for significant improvements in accuracy, as well as its application to spectroscopy of pharmaceutical solids and human prostate tissue.
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