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Pharmaceutical and Biomedical
Applications of Spectroscopy in
the Photon Migration Regime
Tomas Svensson
Doctoral Thesis
2008
Pharmaceutical and Biomedical Applications of Spectroscopy in the Photon Migration Regime a a b a a a a a . a a a
© a
a a . a . a b
ISSN 0281-2762
LRAP-392
ISBN 978-91-628-7469-8
Mere power and mere knowledge exalt human nature, but do not bless it
Francis Bacon (1620)
Abstract
Optical measurement technologies and spectroscopy are of great importance in the modern society. Optical techniques are fre- quently used in for example quantitative analysis of chemical com- position, particle size, velocity and temperature. Near-infrared light is used to determine concentration of active ingredients in pharmaceuticals, laser light is employed in pollution monitoring, the pulse oximeter is used for routine monitoring of arterial oxy- genation in patients during surgery, the police utilise pulsed laser light to determine velocities of cars, and so on. An example of particular importance for industry and science is absorption spectroscopy, i.e. measurements of how materials absorb light of di erent wavelengths (colours). Since light absorp- tion is intimately linked to atomic and molecular structure, the technique is very important in analytical chemistry for analysis of chemical composition. In clear liquids and gases, where light travels in straight lines, such analysis is well developed, and fairly simple. Quantitative analysis relies on the fact that the optical pathlength is known { simply given by the sample dimensions. Unfortunately, absorption spectroscopy becomes signi cantly more di cult in materials exhibiting strong light-scattering (turbid ma- terials), such as pharmaceutical solids and biological tissue. Quan- titative analysis becomes particularly di cult, partly due to the unknown and optical pathlength, and partly due to that light scat- tering often has larger impact on the detected light intensity than does absorption. The present thesis is devoted to two di erent matters: One part is the development of a novel optical technique for characteri- sation of solid pharmaceutical materials. The other part being the continued development of photon time-of- ight spectroscopy, as well as exploration of new application areas of this method. These two optical techniques are conceptually and technically very dif- ferent, 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 ap- plied for chemical analysis and analysis of structural properties of for example pharmaceutical tablets, human prostate tissue, andv
Abstract
female breast tissue. These materials, and many others, scatter light to a much stronger extent than even the densest fog. In a typical pharmaceutical tablet, light is scattered severely enough to completely change its direction each twentieth micrometer. This level of scattering also makes light, on average, travel more than
10 cm when transmitted through a 3 mm thick tablet.
The new optical method for analysis of structure in pharma- ceutical solids, presented in this thesis, 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 in uenced by scattering properties. A moderately compressed tablet of 3 to
4 mm thickness can, due to long optical pathlengths in transmis-
sion, give rise to absorptions corresponding to tens of millimetres through ambient air. The sensitivity to sample structure makes this technique highly interesting in, for example, process monitor- ing. 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, at- mospheric sciences and pollution monitoring. However, the detec- tion of gases within solids and scattering materials is accompanied by several aggravating circumstances, setting special requirements on measurement procedure and instrumentation. While conven- tional use of the technology involves well de ned beamlines and gas cells, this thesis deals with detection of weak intensities of di use light and devastating optical interference. The other part of this thesis is concerned with pharmaceu- tical and medical applications of ultrashort (picosecond scale,
1 10 12s) laser pulses for analysis of chemical composition and
material structure of highly scattering samples. The technique is referred to as time-of- ight spectroscopy or time-resolved spec- troscopy. 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 di erent photons (the ele- mentary particle of light) have travelled di erent distances at the same speed (?0?\). The measurement of the temporal distribution of the detected light (i.e. the photon time-of- ight distribution) allows circumventing the di culties encountered in conventional absorption spectroscopy. The time-of- ight distribution is a direct measure of the previously unknown optical pathlength, and the shape of the distribution can be used for quanti cation of both ab- sorption and scattering. The most important contributions of the present thesis, related to this technique, include the development of sophisticated modelling of light propagation for signi cant im- provements in accuracy, as well as its application to spectroscopyvi
Abstract
of pharmaceutical solids and human prostate tissue. The research concerning pharmaceutical solids is conducted in collaboration with Astra Zeneca R&D, M olndal. The pharmaceu- tical industry is continuously looking for new and improved ana- lytical methods. They are currently particularly interested in fast and non-destructive methods for process monitoring and control. Optical techniques are almost often close to ideal in this context. The interest in prostate spectroscopy is related to the current interest in photodynamic therapy (PDT) of prostate cancer. Clin- ical trials are currently conducted at several locations worldwide. Our research group in Lund has for a long time explored clinical applications of PDT. These e orts have, for example, resulted in a routine PDT treatment of non-melanoma skin cancer at the Lund University Hospital. In collaboration with SpectraCure AB, our group is currently involved in an ongoing clinical trial that inves- tigates the potential of PDT for primary treatment of prostate cancer. The present thesis shows that time-of- ight spectroscopy is a useful and highly reliable technique for prostate spectroscopy, capable of delivering optical and physiological information of great importance to PDT and its dosimetry. This includes quanti ca- tion of absorption, scattering, haemoglobin concentration and tis- sue oxygenation. In addition, this thesis also combines the two technical compo- nents brie y described above. Information on oxygen absorption in combination with direct measurement of photon pathlengths al- low what can be called optical porosimetry - that is, a quantitative measure of the amount of gas- lled pores of solid materials. This approach is an interesting alternative to conventional mercury in- trusion porosimetry, a technique used for characterisation of very diverse materials, from concrete to pharmaceuticals.vii Popul
¨arvetenskaplig
sammanfattningOptisk spektroskopi och m atteknik ar av enorm betydelse f or det moderna samh allet. Dessa metoder nyttjar ljus f or att exempelvis best amma kemisk sammans attning, partikelstorlek, hastighet eller temperatur. Laserljus anv ands f or att m ata luftf ororeningar, pul- soximetern anv ander ljus f or att m ata blodets syres attning hos patienter under operation, och polisen anv ander ljuspulser f or att m ata bilars hastighet, och s a vidare. Ett exempel p a en optisk m atteknik av stor vikt f or b ade indus- tri och vetenskap ar absorptionsspektroskopin, d.v.s. m atningar av hur mycket ett material absorberar olika ljusv agl angder (f arger). Eftersom ljusabsorptionen och dess variation med ljusv agl angd ar knuten till atom- och molekyl-struktur kan tekniken anv andas f or best amning av kemisk sammans attning. I material d ar ljus f ardas r atlinjigt (t.ex. klara v atskor och gaser) ar s adan analys mycket v alutvecklad, och relativt enkel. Kvantitativ analys m ojligg ors av att ljusets v agl angd genom materialet ar k and. I kraftigt ljus- spridande material, s asom farmaceutiska tabletter och pulver eller biologisk v avnad, f orsv aras analysen avsev art. Med ljusspridning menas att ljuset byter riktning p a grund av att det studsar mot olika partiklar. Kvantitativ analys blir speciellt sv ar p a grund av att v agl angden nu ar ok and, och att spridningsegenskaperna ofta har st orre inverkan p a m angden detekterat ljus an vad absorptio- nen har. Denna avhandling omfattar tv a saker; dels utvecklandet av en ny optisk m atteknik f or analys av farmaceutiska fasta material, och dels vidareutveckling av, samt utforskandet av nya anv andningsomr aden f or, den s a kallade tidsuppl osta spek- troskopin. Dessa tv a m attekniker ar helt v asensskilda, och dess gemensamma n amnare ar endast att de b ada ar avsedda f or analys av material d ar ljus sprids kraftigt (d.v.s. byter riktning ofta). I denna avhandling anv ands teknikerna till exempel f or kemisk analys och analys av struktur hos farmaceutiska tabletter, m ansklig prostatav avnad eller m ansklig br ostv avnad. I dessa, ochix
Abstract
m anga andra material, sprids ljus enormt mycket mer kraftigt an i den t ataste dimma. I en typisk farmaceutisk tablett sprids ljuset s a kraftigt att det helt har bytt riktning var tjugonde mikrometer (0.02 mm). Detta resulterar i att medelv agl angden f or ljus som f ardats genom en 3 mm tjock tablett ofta ar over 10 cm. I denna avhandling presenteras en nyutvecklad farmaceutisk m atteknik avsedd f or analys av struktur hos farmaceutiska ma- terial. Tekniken oppnar f or icke-f orst orande m atning av egen- skaper s asom t.ex. porositet. Egenskaperna m ats indirekt genom m atning av den mycket svaga (men m atbara) ljusabsorptionen hos de syremolekyler som ar utspridda i provet. Den totala ljusab- sorptionen av syremolekylerna best ams dock inte bara av provets porositet, utan ocks a av dess ljusspridning. En mindre kompakt tablett med 3-4 mm tjocklek kan p a grund av l ang optisk v agl angd genom provet uppvisa en "syreabsorption" som motsvarar tiotals millimeter genom ren luft. K ansligheten f or provets struktur g or att tekniken ar h ogintressant f or t.ex. processanalys. Vidare kan den bidra med f oruts agelser av viktiga l akemedelsparametrar som frig orelsehastighet och uppl osningshastighet. Tekniken ar baserad p a den ultrak ansliga diodlaser-spektroskopin som anv ands f or gas- analys inom t.ex. atmosf arsforskning och luftf ororeningsanalys. Att detektera gaser inuti fasta och kraftigt spridande material st aller dock v aldigt annorlunda krav p a m atf orfarande och utrust- ning. Den andra best andsdelen i avhandlingen r or farmaceutiska och medicinska till ampningar av ultrakorta laserpulser (miljondelar av en miljondels sekund l anga) f or analys av kemisk sammans attning och materialstruktur hos spridande material. Tekniken kallas ofta tidsuppl ost spektroskopi, men dess engelska namn "time-of- ight spectroscopy" ar mer beskrivande. En kort ljuspuls som skickats in, och f ardats en bit genom ett spridande material kommer vid detektion att upplevas som l angre { detta beroende p a att ljusets olika delar f ardas olika l angt (med samma hastighet). Genom att m ata tidsf ordelningen hos det detekterade ljuset (d.v.s. ljusets ygtid, time-of- ight) kringg as de problem som traditionell ab- sorptionsspektroskopi drabbas av. Tidsf ordelningen ger ett direkt m att p a den tidigare ok anda v agl angden, och ljuspulsens inten- sitetsf ordelning kan anv andas f or kvanti ering av b ade absorp- tion och spridning. Avhandlingens viktigaste bidrag till denna teknologi r or utveckling av so stikerad modellering av ljusutbred- ning, resulterande i kraftigt f orb attrad m atnoggrannhet, samt teknikens speci ka till ampning f or spektroskopi av farmaceutiska material och m ansklig prostatav avnad. Forskningen kring farmaceutiska till ampningar sker i n ara samarbete med Astra Zeneca R&D M olndal. Den farma- ceutiska industrin ar st andigt intresserade av nya och f orb attrade m attekniker, och upplever i dagsl aget ett kraftigt behov av snabba och icke-f orst orande analysmetoder f or processkontroll. Optiskax
Abstract
tekniker ar i det n armaste ideala i detta sammanhang. Intresset f or prostataspektroskopin h anger samman med det h ogaktuella intresset f or fotodynamisk terapi av prostatacancer. I skrivande stund utf ors kliniska pr ovningar av denna behandlings- form p a era h all i v arlden. V ar forskargrupp i Lund har l ange forskat kring fotodynamisk terapi, vilket bl.a. resulterat i fotody- namisk rutinbehandling av hudcancer (f orutom maligna melanom) p a Lunds Universitetssjukhus. I samarbete med SpectraCure AB drivs nu kliniska f ors ok (prim arbehandling av m ansklig prostat- acancer) avsedda att utr ona teknikens potential f or behandling av prostatacancer. Denna avhandling visar att tidsuppl ost spek- troskopi ar en ypperlig m atteknik, kapabel att p alitligt leverera op- tisk och fysiologisk information om ljusabsorption, ljusspridning, blodm angd och blodets syres attning i prostatan. Dessa parametrar ar av yttersta betydelse f or fotodynamisk terapi och dess dosimetri. De tv a teknikerna som diskuterats ovan kombineras dessutom i avhandlingen. Informationen om syreabsorption tillsammans med direkt m atning av ljusets v agl angd m ojligg or vad som kan kallas optisk porosimetri - d.v.s. en kvantiativ m atning av m angden gas- fyllda h aligheter i fasta material. Tekniken utg or ett intressant alternativ till den konventionella kvicksilver-porosimetrin, som anv ands vid karakterisering av vitt skilda material, alltifr an be- tong till farmaceutiska tabletter.xi
List of publications
This thesis is based on the following papers, which will be referred to by their roman numerals in the text.ITime and wavelength resolved spectroscopy of turbid media using light continuum generated in a crystal fiber
A. Abrahamsson, T. Svensson, S. Svanberg
S. Andersson-Engels, J. Johansson and S. Folestad. Optics Express12, 4103-4112 (2004).IIScatter correction of transmission near-infrared spectra by photon migration data: Quantitative analysis of solids A. Abrahamsson, A. L owgren, B. Str omdahl, T. Svensson, S. Andersson-Engels, J. Johansson and S. Folestad. Applied Spectroscopy59, 1381-1387 (2005).IIICharacterization of normal breast tissue heterogeneity using time-resolved near-infrared spectroscopy T. Svensson, J. Swartling, P. Taroni, A. Torricelli,
P. Lindblom, C. Ingvar and S. Andersson-Engels.
Physics in Medicine and Biology50, 2559-2271 (2005).IVPerformance assessment of photon migration instruments: the MEDPHOT protocol A. Pi eri, A. Torricelli, A. Bassi, P. Taroni, R. Cubeddu, H. Wabnitz, D. Grosenick, M. M oller, R. Macdonald, J. Swartling, T. Svensson, S. Andersson-Engels, R.L.P. van Veen, H.J.C.M. Sterenborg, J.M Tualle, H.L. Nghiem,
S. Avrillier, M. Whelan and H. Stamm.
Applied Optics44, 2104-2114 (2005).xiii
List of publications
VLeast-squares support vector machines
modelization for time-resolved spectroscopy F. Chauchard, S. Roussel, J.M. Roger, V. Bellon-Maurel,
C. Abrahamsson, T. Svensson, S. Andersson-Engels,
S. Svanberg.
Applied Optics44, 7091-7097 (2005).VIIn vivooptical characterization of human prostatequotesdbs_dbs9.pdfusesText_15
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