Understanding solid-state transformations during dehydration: new insights using vibrational spectroscopy and multivariate modelling

Many active pharmaceutical ingredients (APIs) have both anhydrate and hydrate forms. Due to the different physicochemical properties of solid forms, the changes in solid-state may result in therapeutic, pharmaceutical, legal and commercial problems. In order to obtain good solid dosage form quality and performance, there is a constant need to understand and control these phase transitions during manufacturing and storage. Thus it is important to detect and also quantify the possible transitions between the different forms. In recent years, vibrational spectroscopy has become an increasingly popular tool to characterise the solid-state forms and their phase transitions. It offers several advantages over other characterisation techniques including an ability to obtain molecular level information, minimal sample preparation, and the possibility of monitoring changes non-destructively in-line. Dehydration is the phase transition of hydrates which is frequently encountered during the dosage form production and storage. The aim of the present thesis was to investigate the dehydration behaviour of diverse pharmaceutical hydrates by near infrared (NIR), Raman and terahertz pulsed spectroscopic (TPS) monitoring together with multivariate data analysis. The goal was to reveal new perspectives for investigation of the dehydration at the molecular level. Solid-state transformations were monitored during dehydration of diverse hydrates on hot-stage. The results obtained from qualitative experiments were used to develop a method and perform the quantification of the solid-state forms during process induced dehydration in a fluidised bed dryer. Both in situ and in-line process monitoring and quantification was performed. This thesis demonstrated the utility of vibrational spectroscopy techniques and multivariate modelling to monitor and investigate dehydration behaviour in situ and during fluidised bed drying. All three spectroscopic methods proved complementary in the study of dehydration. NIR spectroscopy models could quantify the solid-state forms in the binary system, but were unable to quantify all the forms in the quaternary system. Raman spectroscopy models on the other hand could quantify all four solid-state forms that appeared upon isothermal dehydration. The speed of spectroscopic methods makes them applicable for monitoring dehydration and the quantification of multiple forms was performed during phase transition. Thus the solid-state structure information at the molecular level was directly obtained. TPS detected the intermolecular phonon modes and Raman spectroscopy detected mostly the changes in intramolecular vibrations. Both techniques revealed information about the crystal structure changes. NIR spectroscopy, on the other hand was more sensitive to water content and hydrogen bonding environment of water molecules. This study provides a basis for real time process monitoring using vibrational spectroscopy during pharmaceutical manufacturing.

Phylogeny of a taxonomically difficult group and evolution of host location mechanism

The parasitic wasps are one of the largest insect groups and their life histories are remarkably variable. Common to all parasitic wasps is that they kill their hosts, which are usually beetles, butterflies and sometimes spiders. Hosts are often at a larval or pupal stage and live in concealed conditions, such as in plant tissue. Parasitic wasps have two main ways of finding their host. 1) They can detect chemical compounds emitted by damaged plant material or released by larvae living in plant tissue, and 2) detect the larvae by sound vibrations. Even though pupae are immobile and silent, and therefore do not cause vibration, parasitoids have, however, adapted to find passive developmental stages by producing vibration themselves by knocking the substrate with their antennae, and then detecting the echoes with their legs. This echolocation allows a parasitoid to locate its potential hosts that are deeply buried in wood. This study focuses on the relationships of the subfamily Cryptinae (Hymenoptera: Ichneumonidae) and related taxa, and the evolution of host location mechanism. There are no earlier studies of the phylogeny of the Cryptinae, and the position of related taxa are unclear. According to the earlier classification, which is entirely intuitional, the Cryptinae is divided into three tribes: Cryptini, Hemigasterini and Phygadeuontini. Further, these tribes are subdiveded into numerous subtribes. This work, based on molecular characters, shows that the cryptine tribes Cryptini, Phygadeuon¬tini and Hemigasterini come out largely as monophyletic groups, thus agreeing with the earlier classification. The earlier subtribal classification had no support. In addition, it is shown that modified antennal structures are associated with host usage of wood-boring coleopteran hosts. The cryptines have a clear modification series on their antennal tips from a simply tip to a hammer-like structure. The species with strongly modified antennae belong mostly to the tribe Cryptini and they utilise wood-boring beetles as hosts. Also, field observations on insect behaviour support this result.

Sneutrino-antisneutrino oscillations at colliders

Modern elementary particle physics is based on quantum field theories. Currently, our understanding is that, on the one hand, the smallest structures of matter and, on the other hand, the composition of the universe are based on quantum field theories which present the observable phenomena by describing particles as vibrations of the fields. The Standard Model of particle physics is a quantum field theory describing the electromagnetic, weak, and strong interactions in terms of a gauge field theory. However, it is believed that the Standard Model describes physics properly only up to a certain energy scale. This scale cannot be much larger than the so-called electroweak scale, i.e., the masses of the gauge fields W^+- and Z^0. Beyond this scale, the Standard Model has to be modified. In this dissertation, supersymmetric theories are used to tackle the problems of the Standard Model. For example, the quadratic divergences, which plague the Higgs boson mass in the Standard model, cancel in supersymmetric theories. Experimental facts concerning the neutrino sector indicate that the lepton number is violated in Nature. On the other hand, the lepton number violating Majorana neutrino masses can induce sneutrino-antisneutrino oscillations in any supersymmetric model. In this dissertation, I present some viable signals for detecting the sneutrino-antisneutrino oscillation at colliders. At the e-gamma collider (at the International Linear Collider), the numbers of the electron-sneutrino-antisneutrino oscillation signal events are quite high, and the backgrounds are quite small. A similar study for the LHC shows that, even though there are several backrounds, the sneutrino-antisneutrino oscillations can be detected. A useful asymmetry observable is introduced and studied. Usually, the oscillation probability formula where the sneutrinos are produced at rest is used. However, here, we study a general oscillation probability. The Lorentz factor and the distance at which the measurement is made inside the detector can have effects, especially when the sneutrino decay width is very small. These effects are demonstrated for a certain scenario at the LHC.

Towards Understanding Powder Behavior Via Simulation

The aim of this study was to investigate powder and tablet behavior at the level of mechanical interactions between single particles. Various aspects of powder packing, mixing, compression, and bond formation were examined with the aid of computer simulations. The packing and mixing simulations were based on spring forces interacting between particles. Packing and breakage simulations included systems in which permanent bonds were formed and broken between particles, based on their interaction strengths. During the process, a new simulation environment based on Newtonian mechanics and elementary interactions between the particles was created, and a new method for evaluating mixing was developed. Powder behavior is a complicated process, and many of its aspects are still unclear. Powders as a whole exhibit some aspects of solids and others of liquids. Therefore, their physics is far from clear. However, using relatively simple models based on particle-particle interaction, many powder properties could be replicated during this work. Simulated packing densities were similar to values reported in the literature. The method developed for describing powder mixing correlated well with previous methods. The new method can be applied to determine mixing in completely homogeneous materials, without dividing them into different components. As such, it can describe the efficiency of the mixing method, regardless of the powder's initial setup. The mixing efficiency at different vibrations was examined, and we found that certain combinations of amplitude, direction, and frequencies resulted in better mixing while using less energy. Simulations using exponential force potentials between particles were able to explain the elementary compression behavior of tablets, and create force distributions that were similar to the pressure distributions reported in the literature. Tablet-breaking simulations resulted in breaking strengths that were similar to measured tablet breaking strengths. In general, many aspects of powder behavior can be explained with mechanical interactions at the particle level, and single particle properties can be reliably linked to powder behavior with accurate simulations.