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Browsing by Subject "Raman"

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  • Rojalin, Tatu (2015)
    Raman spectroscopy is based on vibrations that occur between the atoms of a compound. The overall structural energy is derived from the electronical energy as well as vibrational, rotational and translational energy. In Raman spectroscopy the vibrational and rotational energies are essential. Usually the excitation energy used in Raman spectroscopy can be either in the region of visible light or NIR. The sample absorbs the energy and energy is also scattered back to all possible directions. Elastic scattering is called the Rayleigh scattering. In that case the back-scattered photons have an equal energy as the original excitation energy. However, some of the scattering happens inelastically and it forms the basis of Raman-phenomena. If the detected photons have smaller energy than the original, it is called the Stokes scattering. If the energy is bigger, it is anti-Stokes scattering. Raman is typically very rare and weak phenomenon. The spectral features in Raman spectra consist of the intensities and energies of the back scattered photons. Raman spectroscopy provides very accurate and detailed structural information on the molecule. It is basically a label-free technique with minimal need for sample preparation and the measurements can also be carried out e.g. through container walls. Further, Raman is quite insensitive to hydrous samples and it is suitable to solutions and biological assessments. However, there are some drawbacks that are formed by the luminescence phenomena i.e. fluorescence. Strong fluorescent backgrounds can mask the relevant Raman features in spectra because Raman and fluorescence are competetive processes. For instance many drug molecules have such structures that they cause strong fluorescence. It is also one of the reasons that pharmaceutical applications and measurements have been partly limited due to this problem. There are applications to improve and enhance a Raman signal. For example resonance phenomena and SERS are favored. To solve the fluorescence-related problems there are also means; one can change the laser wavelenght, photobleach the sample or apply different kinds of data manipulation techniques to the spectral data achieved. There are drawbacks with these methods. They can be slow, complex, damage the samples and still insufficient fluorescence suppression is a problem. In this study a novel time-gated CMOS-SPAD detection technique is applied to non-fluorescent and fluorescent drug measurements. The new detection system has a programmable on-chip delay time and it is synchronized with a picosecond pulsed laser. The scattered photons can be measured in the time scale when they are simultaneously measured in traditional energy and intensity wise. Raman scattering occurs in the timescale of sub-picoseconds while the fluorescence phenomena happen typically in the order of nanoseconds. This time difference can be exploited effectively to suppress the fluorescence. In the literature review of this study the basis of vibrational spectroscopy is introduced - especially Raman spectroscopy. The techniques related, as well as the novel time-resolved technique are covered. Further, different kinds of applications in the field of Raman spectroscopy are reviewed, mainly pharmaceutics-related and biologically relevant applications. In the experimental work the focus was to compare a continuous-wave 785 nm laser setup coupled with the CCD-detector to the pulsed picosecond 523 nm laser coupled with the CMOS-SPAD-detector. The measurements were performed on different kinds of drugs, both non-fluorescent and fluorescent. The aim was to obtain information on the effectiveness of CMOS-SPAD-technique on fluorescence suppression for solid drugs and solutions. Secondary goals were to collect knowledge on the similarities and differences between the Raman setups used for solution measurements, to optimize and discuss the key elements of setups for solids and solutions and to show preliminarily the applicability of the CMOS-SPAD-system on fluorescent drug's solutions as well as find out the requirements related to quantitative assessments using Raman spectroscopy. In drug research there is also constant need for reliable in vitro cell assays. The assessments made in this study may prove useful to the future applications e.g. measurements with living cells. An effective fluorescence suppression was achieved to strong fluorescent backgrounds using the novel time-resolved CMOS-SPAD-detection system coupled with the pulsed picosecond 532 nm laser. The setup is potentially a convenient tool to overcome many fluorescence-related limitations of Raman spectroscopy for laboratory and process analytical technology (PAT) use in the pharmaceutical setting. The results achieved encourage to consider that with careful calibration and method validation there is potential for quantitative analysis, biopharmaceutical and biological applications e.g. in vitro cell studies where most Raman techniques suffer from strong fluorescence backgrounds. Other potential fields for future applications can be also considered.
  • Savolainen, Heikki (2018)
    Tablet manufacturing requires both high-quality equipment and powder blend with high flowability and compactability and low segregation tendency. The process is complex and tablet formation process still remains not fully understood. Adequate powder flow is a necessity for the pharmaceutical manufacturing process, i.e., powder flowability and flow properties play a great role when designing manufacturing processes for solid dosage forms. As such, the powder characteristics need to be investigated. However, one property is seldom enough to predict the flowability of a powder in specific processes and different test methods need to be used to fully understand the tableting performance of a particular powder. It is crucial to know how the assessed properties reflect the manufacturing conditions. The need for test batches and the use of empirical testing still exists despite the numerous powder characterization tests available. The main aim of the study was to understand the influence of material properties, flow properties and segregation tendencies on both the processability of a formulation during tablet compression and the critical quality attributes, such as mass, tensile strength and dose uniformity of the final drug product. Additionally, testing of an in-line NIR method to observe the homogeneity of the powder inside the force feeder right before the compression step and transmission Raman as an at-line method for tablet content were also evaluated. A number of powder characterization tests were employed in order to fully understand the impact of the formulation on the process performance. Three formulations with different particle size of the active substance and mannitol were used throughout the study. Both the sifting segregation and fluidization segregation tests’ results predicted the formulations’ tabletability particularly well. Fluidization segregation test predicted the changing composition of the formulation throughout tableting whereas sifting segregation results showed the constantly fluctuating API concentration in the manufactured tablets. Moreover, the Raman results confirmed the tablets of variable content despite the offset caused by the different particle size of the raw materials used. The functionality of the NIR in the force feeder was tested successfully. The residence time distribution could be determined at a sufficient level to point out tablets of a bad quality from the batch on grounds of the NIR data. Results from the powder flow property tests were rather conflicting. Angle of repose, Carr’s index and volume flow rate gave the best characterizing results, whereas the mass flow rate, shear test with higher normal stress in pre-shear gave the worst results, considering the experienced flow character of the formulations. As stated above, different flow property tests may give conflicting result, and hence, it is crucial to know which results are the most relevant ones. Furthermore, the right settings for the test should be known to gain applicable results, best exemplified by the shear cell test.