Reinheitskontrolle von pharmazeutischen und chemischen Stoffen für die Anwendung im Prozess im mittleren und nahen Infrarot [Elektronische Ressource] / Kondagula Fayaz. Gutachter: Heinz Wilhelm Siesler. Betreuer: Karl Molt

Informations

• Publié par: universitat_duisburg-essen
• Publié le: 01 janvier 2011
• Nombre de lectures: 21
• Langue: English
• Poids de l'ouvrage: 40 Mo

Extrait

Purity Control of Pharmaceutical and Chemical
Substances for Application in Process
Environments using Spectroscopy in the Middle
and Near Infrared
Instrumentelle Analytische Chemie
Fakult at fur Chemie
der Universit at Duisburg-Essen
Zur Erlangung des akademischen Grades eines
Doktors der Naturwissenschaften
Dr. rer. nat
genehmigte Dissertation
vorgelegt von
Fayaz Kondagula
aus
Hyderabad, Indien
Referent: Prof. Dr. Karl Molt
Korreferent: Prof. Dr. H. W. Siesler
Vorsitzender: : Prof. Dr. Thomas Schrader
Tag der mundlic hen Prufung: 19 April 2011
iDeclaration
I herewith declare that I have produced this thesis without the pro-
hibited assistance of third parties and without making use of aids
other than those speci ed; notions taken over directly or indirectly
from other sources have been identi ed as such. This thesis has not
previously been presented in identical or similar form to any other
German or foreign examination board.
The thesis work was conducted from 01.12.2007 to 30.12.2010 under
the supervision of Prof. Dr. Karl Molt at the department of Instru-
mental Analytical Chemistry in University-Duisburg Essen.
(Fayaz Kondagula)
Essen.Dedicated
To my parents K. Khadeer Saheb, K. Tamijunnisa
Begum and my guru Prof. Dr. Karl MoltAcknowledgements
Foremost, I express my sincere gratitude to my advisor Prof. Dr. Karl
Molt for the continuous support of my PhD study and research, for
his patience, motivation, enthusiasm, and immense knowledge. His
guidance helped me in all the time of research and writing of this
thesis. I could not have imagined having a better advisor and mentor
for my PhD study.
Besides my advisor, I would like to thank Prof. Dr. H. W. Siesler for
being my co-referee.
I thank Mr. Wolfgang Ritter, CEO of QuantaRed Technogies GmbH
(Vienna), for the opportunity to take measurements with the ER-
ACHECK instrument.
My special thanks to my lab mate and colleague Dr. Jessica Trockel.
Her discipline was a great inspiration for completion of my thesis.
My sincere thanks to my colleagues of the Department Instrumental
Analytical Chemistry especially Robert Knerim and Lydia Vassen.
Special thanks to my friends and wonderful human beings Srinivas
Satyanarayana, Chitumalla Ramesh, Meike Stute, Syed Ansar Basha,
Sreedhar Nagandla and Abdul Kareem Ragaz who made life more
bright and sunny. I would like to express my sincere gratitude to
my beloved parents Khadeer Saheb and Tamijunnisa Begum and my
three sisters Nazneen, Nasreen and Nadiya who were the real source
of inspiration and emotional support which have enabled to complete
this work with success.
I would like to acknowledge the thousands of individuals who have
Acoded for the R-Project and LT X project for free. Last but notE
least I would like to ask for an excuse to the other individuals who
supported me whom I could not mention due shortage of space.
Finally I would like end this acknowledgment by a proverb around
which the life of a Analytical Chemist revolves:\Vertrauen ist gut, Kontrolle ist besser"Abstract
All organic and most inorganic compounds show characteristic In-
frared spectra. Therefore IR Spectroscopy can be used as an e ective
tool for quality control. Middle and Near Infrared with modern instru-
mentation and accessories like Diamond ATR and Di use Re ectance
accessories, provide spectra which are highly reproducible making it
possible to detect even minor spectral deviations caused by impuri-
ties. In this thesis the focus is on quality control in chemical process
environments where the purity of materials has to be determined more
or less automatically.
The correlation between the spectrum of a potentially contaminated
sample and the reference spectrum of the corresponding pure com-
pound can be used as measure for purity in terms of the correlation
coe cient r. r is obtained by regressing the sample spectrum on the
reference spectrum. A simulation study showed that it is advanta-
geous to transformr to Fisher’sz coe cient because z is much better
suited than r for detecting small spectral deviations caused by im-
purities. On this basis two spectral purity parameters SPR and1
SPR were obtained by multiplying the correlation coe cient resp.2
the normalized z coe cient with 100.
As a second way for discovering impurities a method of dynamic dif-
ference spectroscopy was developed, by which the di erence between
the spectrum of the sample and the reference and the corresponding
di erence factor are calculated automatically. As spectral purity pa-
rameters the obtained di erence factor itself, SPR , and alternatively3
the integral of the di erence spectrum, SPR , are used.4
The methods based on linear regression proved to be more e ectual
and detection limits of impurities down to 0.002 g/100 g for liquids
and 0.03 g/100 g for solids could be achieved. Further it could be
shown that by using a Quantum Cascade Laser spectrometer instead
of a FT-IR instrument still lower limits of detection can be attained.Contents
List of Figures v
List of Tables xii
1 Introduction and Objectives 1
1.1 Infrared Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1.1 Direct Evidence on Constitution . . . . . . . . . . . . . . . 2
1.1.2 Identi cation by Spectral Comparison . . . . . . . . . . . . 3
1.2 Motivation and Objective . . . . . . . . . . . . . . . . . . . . . . 4
2 Theory and basic principles of MIR/NIR-spectroscopy 8
2.1 The electromagnetic spectrum . . . . . . . . . . . . . . . . . . . . 8
2.1.1 Molecular vibrations . . . . . . . . . . . . . . . . . . . . . 9
2.1.2 Harmonic and anharmonic oscillator . . . . . . . . . . . . 10
2.2 Spectrometers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.2.1 Spectrometers as tools for quantitative analysis and purity
control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.2.2 FT-IR spectrometers . . . . . . . . . . . . . . . . . . . . . 15
2.2.3 Radiation sources . . . . . . . . . . . . . . . . . . . . . . . 16
2.2.4 IR Detectors . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.3 Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.3.1 Attenuated Total Re ectance (ATR) . . . . . . . . . . . . 20
2.3.2 Di use re ection . . . . . . . . . . . . . . . . . . . . . . . 22
2.4 Limit of detection, capture and quanti cation . . . . . . . . . . . 24
2.4.1 Blank value method . . . . . . . . . . . . . . . . . . . . . 24
iCONTENTS
2.4.2 Calibration line method . . . . . . . . . . . . . . . . . . . 25
3 Materials and software 27
3.1 Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1.1 FT-IR Spectrometer . . . . . . . . . . . . . . . . . . . . . 27
3.1.2 Diamond ATR Unit . . . . . . . . . . . . . . . . . . . . . . 28
3.1.3 NIR Spectrometer . . . . . . . . . . . . . . . . . . . . . . 28
3.1.4 Eracheck Spectrometer with QCL-IR technology . . . . . . 29
3.1.5 Auxiliary accessories . . . . . . . . . . . . . . . . . . . . . 29
3.2 Software . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.2.1 Software for acquiring spectra . . . . . . . . . . . . . . . . 30
3.2.2 Software for analysis of spectra . . . . . . . . . . . . . . . 30
4 Development of spectral purity parameters and a simulated ex-
ample 32
4.1 Spectral purity parameters based on linear regression . . . . . . . 32
4.1.1 Correlation coe cient . . . . . . . . . . . . . . . . . . . . 33
4.1.2 Distribution of r . . . . . . . . . . . . . . . . . . . . . . . 35
4.1.3 Fisher’s z transformation . . . . . . . . . . . . . . . . . . . 37
4.2 Spectral purity parameters based on di erence spectroscopy . . . 40
4.3 Testing the spectral purity parameters SPR and SPR with a1 2
simulated example . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4.3.1 Limit of detection (LOD) and limit of capture (LOC) for
the impurity . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.3.2 In uence of noise on limits of detection and capture . . . . 42
5 Application of the developed spectral purity parameters to ex-
perimental models 45
5.1 Purity control of Palatinol-N . . . . . . . . . . . . . . . . . . . . . 46
5.1.1 Spectral purity control employing Middle IR
Palatinol-AH as impurity in Palatinol-N . . . . . . . . . . 47
5.1.1.1 Preparation of samples . . . . . . . . . . . . . . . 47
5.1.1.2 Recording of spectra . . . . . . . . . . . . . . . . 48
iiCONTENTS
5.1.1.3 Analysis of spectra by calculating spectral purity
parameters . . . . . . . . . . . . . . . . . . . . . 49
5.1.1.4 Quantitative analysis . . . . . . . . . . . . . . . . 54
5.1.2 Spectral purity control employing Near-IR
Palatinol-AH as impurity in Palatinol-N . . . . . . . . . . 57
5.1.3 Spectral purity control employing Middle-IR
Palatinol-911P as impurity in Palatinol-N . . . . . . . . . 59
5.1.3.1 Preparation of samples and recording of spectra . 59
5.1.3.2 Analysis of spectra by calculating spectral purity
parameters . . . . . . . . . . . . . . . . . . . . . 59
5.1.3.3 Quantitative analysis . . . . . . . . . . . . . . . . 60
5.1.4 Spectral purity control employing Near-IR
Palatinol-911P as impurity in Palatinol-N . . . . . . . . . 61
5.1.4.1 Preparation of samples and recording of spectra . 61
5.1.4.2 An