M.Sc. (Chemistry) / A brief discussion of gas-solid interactions is given. The choice of reflection-absorption infrared spectroscopy (RAIRS) and the Kelvin probe as surface analytical techniques resulted in a visit to the physical research laboratory of Prof. J, Pritchard at Queen Mary College (London) . At this laboratory the author took part in the development of a wavelength modulation spectrometer. A spectrometer in the RAIRS mode and a Kelvin probe were used to study the adsorption of CO on a Cu(110) single crystal ...

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Cleaning validation, in which cleaned surfaces are analysed for residual material, is an important process in pharmaceutical manufacturing and research facilities. Current procedures usually consist of either swab or rinse-water sampling followed by analysis of the samples. The analysis step is typically either rapid but unselective (conductivity, pH, total organic carbon, etc.), or selective but time-consuming (HPLC). This thesis describes the development of an in situ surface-spectroscopic analysis that removes the need for swab sampling and is both rapid and selective. This method has the potential to complement existing analyses to increase the efficiency of cleaning-validation protocols. The spectrometric system consists of a Fourier-transform infrared (FTIR) spectrometer coupled to a fibre-optic grazing-angle reflectance probe, and allows the measurement of infrared reflection-absorbance spectra (IRRAS) from flat surfaces in ~10 s. Multivariate chemometric methods, such as partial least squares (PLS) regression, are used to exploit the high information content of infrared spectra to obtain selective analyses without physical separation of the analyte or analytes from whatever interfering species may be present. Multivariate chemometric models require considerably more effort for calibration and validation than do traditional univariate techniques. This thesis details suitable methods for preparing calibration standards by aerosol deposition, optimising and validating the model by cross- and test-set validation, and estimating the uncertainty by resampling and formula-based approaches. Successful calibration models were demonstrated for residues of acetaminophen, a model active pharmaceutical ingredient (API), on glass surfaces. The root-mean-square error of prediction (RMSEP) was ~0.07 µg cm⁻². Simultaneous calibration for acetaminophen and aspirin, another API, gave a similar RMSEP of 0.06 µg cm⁻² for both compounds, demonstrating the selectivity of the method. These values correspond to detection limits of ~0.2 µg cm⁻², well below the accepted visual detection limit of ~1-4 µg cm⁻². The sensitivity of the method with a stainless steel substrate was found to depend strongly on the surface finish, with highly polished surfaces giving more intense IRRAS. RMSEP values of 0.04- 0.05 µg cm⁻² were obtained for acetaminophen on stainless steel with three different finishes. For this system, severe nonlinearity was encountered for loadings 1.0 µg cm⁻². From the results presented in this thesis, it is clear that IRRAS has potential utility in cleaning validation as a complement to traditional techniques.

In order to implement an accurate system that allows for absorption of reflected waves impinging to a wave maker (Active Reflection Absorption), it was required to apply a method to estimate properly the direction of arrival of the waves that does it in the fastest way possible. Our wavemaker control system has been prepared to handle an algorithm provided by Bosch-Rexroth where the wave angle estimation is practically locked to a very narrow frequency band (spatial gain-mixer). The system was evaluated with physical tests in a 3D wave basin for different conditions of reflected waves arriving with an angle to the wavemaker front, and acceptable performance has been found for the 3D ARA mode. However, for certain conditions over-compensation or sub-compensation can develop resulting in a poor absorption. This is mainly related to not being able to determine accurately the direction from which the reflected waves travel towards the wavemaker. The present work employed concepts found in the areas of antenna array signal processing and signal propagation, which were applied to this problem. This approach coupled naturally with our wavemaker system since it was prepared with 48 gages that can be employed in an array antenna fashion. A program was codified from an algorithm found in literature to calculate the Direction of Arrival (DOA) of the reflected waves. The focus for the testing of this program was with regular waves. The tests were conducted to validate the program with different angles of incidence and show that for regular waves the program was able to detect accurately the DOA of these in as few as 5 snapshots, with a minimum of 7 gages used as the antenna input. With data obtained directly from the control system of our wavemaker using regular waves, the program was able to determine the DOA. The computational burden of the algorithm is not significant in the case of regular waves. A modification of the program is required to analyze the DOA of reflected irregular waves, which could increase the computational burden. Actual implementation of this program to our control system depends on cooperation with Bosch-Rexroth.

Cleaning validation, in which cleaned surfaces are analysed for residual material, is an important process in pharmaceutical manufacturing and research facilities. Current procedures usually consist of either swab or rinse-water sampling followed by analysis of the samples. The analysis step is typically either rapid but unselective (conductivity, pH, total organic carbon, etc.), or selective but time-consuming (HPLC). This thesis describes the development of an in situ surface-spectroscopic analysis that removes the need for swab sampling and is both rapid and selective. This method has the potential to complement existing analyses to increase the efficiency of cleaning-validation protocols. The spectrometric system consists of a Fourier-transform infrared (FTIR) spectrometer coupled to a fibre-optic grazing-angle reflectance probe, and allows the measurement of infrared reflection-absorbance spectra (IRRAS) from flat surfaces in ~10 s. Multivariate chemometric methods, such as partial least squares (PLS) regression, are used to exploit the high information content of infrared spectra to obtain selective analyses without physical separation of the analyte or analytes from whatever interfering species may be present. Multivariate chemometric models require considerably more effort for calibration and validation than do traditional univariate techniques. This thesis details suitable methods for preparing calibration standards by aerosol deposition, optimising and validating the model by cross- and test-set validation, and estimating the uncertainty by resampling and formula-based approaches. Successful calibration models were demonstrated for residues of acetaminophen, a model active pharmaceutical ingredient (API), on glass surfaces. The root-mean-square error of prediction (RMSEP) was ~0.07 µg cm⁻². Simultaneous calibration for acetaminophen and aspirin, another API, gave a similar RMSEP of 0.06 µg cm⁻² for both compounds, demonstrating the selectivity of the method. These values correspond to detection limits of ~0.2 µg cm⁻², well below the accepted visual detection limit of ~1-4 µg cm⁻². The sensitivity of the method with a stainless steel substrate was found to depend strongly on the surface finish, with highly polished surfaces giving more intense IRRAS. RMSEP values of 0.04- 0.05 µg cm⁻² were obtained for acetaminophen on stainless steel with three different finishes. For this system, severe nonlinearity was encountered for loadings 1.0 µg cm⁻². From the results presented in this thesis, it is clear that IRRAS has potential utility in cleaning validation as a complement to traditional techniques.

Cleaning validation of pharmaceutical manufacturing equipment is required by legislation. Generally, wet chemical techniques are employed using swabbing and/or rinse sampling methods. These are generally either selective and time consuming, or less selective and give results in a shorter period. The infrared reflection absorption spectroscopy (IRRAS) technique explored here attempts to deliver accurate, selective surface contamination information in real time to complement current methods and reduce down-time. The IRRAS instrument used in this research is a Fourier transform infrared (FTIR) spectrometer coupled by an IR fibre-optic cable to a grazing-angle sampling head with a fixed incidence angle of 80°. The introduced flexibility permits collection of in situ spectra from contaminated surfaces. Calibration models are developed using the multivariate, linear partial least squares (PLS) statistical method. The research focuses on sodium dodecyl sulfate (SDS), a model cleaning agent, on metal (aluminium and stainless steel) and dielectric (glass, EPDM and silicone) surfaces. The effects of surface finish are investigated for SDS on stainless steel. Calibrations for SDS and paracetamol in the presence of each other on glass surfaces are examined, as well as a common industrial cleaner (P3 cosa® PUR80) on polished stainless steel. For the calibration sets in this thesis, RMSECV values were < 0.41 µg cm⁻², corresponding to conservative surface residues detection limits of better than ~0.86 µg cm⁻². However, RMSECV values depend on the calibration loading range, and the detection limits were typically ~0.2 µg cm⁻² for loading ranges 0-2.5 µg cm⁻². These are below visual detection limits, generally taken to be 1-4 µg cm⁻², depending on the analyte and substrate. This shows that IRRAS is a viable method for the real-time detection and quantification of surface contamination by surfactants and active pharmaceutical ingredients on metals and dielectrics.

<p>Immobilization of different bio- and organic molecules on solid supports is fundamental within many areas of science. Sometimes, it is desirable to obtain a directed orientation of the molecule in the immobilized state. In this thesis, the copper (I) catalyzed Huisgen 1,3-dipolar cycloaddition, referred to as a “click chemistry” reaction, was explored as a means to perform directed immobilization of small molecule ligands on gold surfaces. The aim was to synthesize alkyne- and azide-terminated alkanethiols that would form well-organized self assembled monolayers (SAMs) on gold from the commercially available substances orthoethylene glycol and bromo alkanoic acid. N-(23-azido-3,6,9,12,15,18,21-heptaoxatricosyl)-n-mercaptododekanamide/hexadecaneamide (n = 12, 16) were successfully synthesized and allowed to form SAMs of different compositions to study how the differences in density of the functional groups on the surface would influence the structure of the monolayer and the click chemistry reaction. The surfaces were characterized by different optical methods: ellipsometry, contact angle goniometry and infrared reflection-absorption spectroscopy (IRAS). The click reaction was found to proceed at very high yields on all investigated surfaces. Finally, the biomolecular interaction between a ligand immobilized by click chemistry on the gold surfaces and a model protein (bovine carbonic anhydrase) was demonstrated by surface plasmon resonance using a Biacore system.</p>

Immobilization of different bio- and organic molecules on solid supports is fundamental within many areas of science. Sometimes, it is desirable to obtain a directed orientation of the molecule in the immobilized state. In this thesis, the copper (I) catalyzed Huisgen 1,3-dipolar cycloaddition, referred to as a “click chemistry” reaction, was explored as a means to perform directed immobilization of small molecule ligands on gold surfaces. The aim was to synthesize alkyne- and azide-terminated alkanethiols that would form well-organized self assembled monolayers (SAMs) on gold from the commercially available substances orthoethylene glycol and bromo alkanoic acid. N-(23-azido-3,6,9,12,15,18,21-heptaoxatricosyl)-n-mercaptododekanamide/hexadecaneamide (n = 12, 16) were successfully synthesized and allowed to form SAMs of different compositions to study how the differences in density of the functional groups on the surface would influence the structure of the monolayer and the click chemistry reaction. The surfaces were characterized by different optical methods: ellipsometry, contact angle goniometry and infrared reflection-absorption spectroscopy (IRAS). The click reaction was found to proceed at very high yields on all investigated surfaces. Finally, the biomolecular interaction between a ligand immobilized by click chemistry on the gold surfaces and a model protein (bovine carbonic anhydrase) was demonstrated by surface plasmon resonance using a Biacore system.

Cleaning validation of pharmaceutical manufacturing equipment is required by legislation. Generally, wet chemical techniques are employed using swabbing and/or rinse sampling methods. These are generally either selective and time consuming, or less selective and give results in a shorter period. The infrared reflection absorption spectroscopy (IRRAS) technique explored here attempts to deliver accurate, selective surface contamination information in real time to complement current methods and reduce down-time. The IRRAS instrument used in this research is a Fourier transform infrared (FTIR) spectrometer coupled by an IR fibre-optic cable to a grazing-angle sampling head with a fixed incidence angle of 80°. The introduced flexibility permits collection of in situ spectra from contaminated surfaces. Calibration models are developed using the multivariate, linear partial least squares (PLS) statistical method. The research focuses on sodium dodecyl sulfate (SDS), a model cleaning agent, on metal (aluminium and stainless steel) and dielectric (glass, EPDM and silicone) surfaces. The effects of surface finish are investigated for SDS on stainless steel. Calibrations for SDS and paracetamol in the presence of each other on glass surfaces are examined, as well as a common industrial cleaner (P3 cosa® PUR80) on polished stainless steel. For the calibration sets in this thesis, RMSECV values were < 0.41 µg cm⁻², corresponding to conservative surface residues detection limits of better than ~0.86 µg cm⁻². However, RMSECV values depend on the calibration loading range, and the detection limits were typically ~0.2 µg cm⁻² for loading ranges 0-2.5 µg cm⁻². These are below visual detection limits, generally taken to be 1-4 µg cm⁻², depending on the analyte and substrate. This shows that IRRAS is a viable method for the real-time detection and quantification of surface contamination by surfactants and active pharmaceutical ingredients on metals and dielectrics.

No description available.