This thesis describes the development of an empirical model of focus beam reflectance measurements (FBRM) and the application of the model to monitoring batch cooling crystallization and extracting information on crystallization kinetics. Batch crystallization is widely used in the fine chemical and pharmaceutical industries to purify and separate solid products. The crystal size distribution (CSD) of the final product greatly influences the product characteristics, such as purity, stability, and bioavailability. It also has a great effect on downstream processing. To achieve a desired CSD of the final product, batch crystallization processes need to be monitored, understood, and controlled. FBRM is a promising technique for in situ determination of the CSD. It is based on scattering of laser light and provides a chord-length distribution (CLD), which is a complex function of crystal geometry. In this thesis, an empirical correlation between CSDs and CLDs is established and applied in place of existing first-principles FBRM models. Built from experimental data, the empirical mapping of CSD and CLD is advantageous in representing some effects that are difficult to quantify by mathematical and physical expressions. The developed model enables computation of the CSD from measured CLDs, which can be followed during the evolution of the crystal population during batch cooling crystallization processes. Paracetamol, a common drug product also known as acetaminophen, is selected as the model compound in this thesis study. The empirical model was first established and verified in a paracetamol-nonsolvent (toluene) slurry, and later applied to the paracetamol-ethanol crystallization system. Complementary to the FBRM measurements, solute concentrations in the liquid phase were determined by in situ infrared spectra, and they were jointly implemented to monitor the crystallization process. The framework of measuring the CSD and the solute concentration allows the estimation of crystallization kinetics, including those for primary nucleation, secondary nucleation, and crystal growth. These parameters were determined simultaneously by fitting the full population balance model to process measurements obtained from multiple unseeded paracetamol-ethanol crystallization runs. The major contributions of this thesis study are (1) providing a novel methodology for using FBRM measurements to estimate CSD; (2) development of an experimental protocol that provided data sets rich in information on crystal growth and primary and secondary nucleation; (3) interpretation of kinetics so that appropriate model parameters could be extracted from fitting population balances to experimental data; (4) identification of the potential importance of secondary nucleation relative to primary nucleation. The protocol and methods developed in this study can be applied to other systems for evaluating and improving batch crystallization processes.

Doctor of Philosophy / Food Science Institute / Jayendra K. Amamcharla / Lactose is commercially produced from whey, whey permeate, or milk permeate as α-lactose monohydrate in crystalline form. Focused Beam Reflectance Measurement (FBRM) as a potential tool for in situ monitoring of lactose crystallization at concentrations relevant to the dairy industry was evaluated. Applicability of FBRM at supersaturated lactose concentrations 50%, 55%, and 60% (w/w) was reported in comparison with Brix values obtained from a Refractometer during isothermal crystallization at temperatures 20ºC and 30ºC. FBRM technique was shown to be a valuable tool for monitoring chord length distributions during lactose crystallization. In a different study, the influence of cooling rate during crystallization of lactose in concentrated permeates was studied. Three cooling rates accounting for approximately 17, 11, and 9 h were applied during lactose crystallization to evaluate the lactose crystal yield and quality of lactose crystals. There was no significant difference (P>0.05) found in lactose crystal yield, mean particle size obtained at the end of crystallization. This study suggested that increasing the cooling rate during lactose crystallization within the range explained in this study can save approximately 8 h of crystallization time. These studies evaluated FBRM as a potential tool to monitor lactose crystal chord lengths and counts. Also, process improvements were suggested to increase the productivity of lactose crystallization process by reducing the crystallization time. In chapters 5 and 6, calcium-reduced milk protein concentrates (MPCs) were used as an ingredient to improve the stability of high-protein dairy beverages. Heat stability increased significantly (P>0.05) in 8% protein solutions made from 20% calcium-reduced MPC. A significant increase in heat stability was observed in beverages formulated with 20% calcium-reduced MPC in the absence of chelating agent. In another study, it was evident that the dairy beverage formulation with 20% calcium-reduced MPC showed no sedimentation and age gelation indicating an improved storage stability. These studies confirmed that 20% calcium reduced MPC contributed towards improved heat stability and storage stability of the high-protein beverages.

Cette thèse porte sur l’étude d’une nouvelle source de particules chargées peu dispersive basée sur le refroidissement d’atomes par laser. Les technologies actuelles, basées sur des pointes fines de quelques nanomètres, sont limitées à des faisceaux de hautes énergies (champ d’accélération supérieur à 10 kV) et de fortes dispersions supérieures à 1 eV du fait des fortes interactions entre les particules se retrouvant très proches les unes des autres au moment de leur création. Une nouvelle source, basée sur un jet atomique refroidi transversalement et ionisé par lasers, permet d’étendre la zone de création des particules chargées à des dimensions de quelques centaines de micron et ainsi de limiter les intéractions entre les particules, tout en créant une source refroidie à 100 µK et ainsi très peu dispersive. Un guidage, utilisant la force dipolaire exercée par un laser appliqué le long de la propagation des atomes, est étudié expérimentalement et permet de piéger les atomes au centre du laser piégeur. En jouant sur la forme du laser, il est ainsi possible de concentrer les atomes dans une section de diamètre de l’ordre de 0,4 mm. Il est dès lors envisageable de créer une source de particules chargées avec des courants supérieurs au nA. L’ionisation des atomes du jet refroidi, basée sur l’ionisation d’atomes de Rydberg sous champ, est étudiée et comparée aux récentes expériences de photoionisation d’atomes refroidis dans un MOT-3D. / This thesis presents the creation of charged-particle beam based on a source with a low energy spread. Common sources, based on thin nanometer-size needle, allows to create charged-particles beams with a high energy (electric higher than 10 kV are used) and with a high energy spread (higher than 1 eV) due to interactions between particles created close to each other. A new source, based on an atomic beam cooled transversaly and ionized using lasers, allows to extend the size of the source until 100 µm and limit the interactions between particles while creating a cold source with temperatures as low as few 100 µK and thus with a low energy spread. A guiding laser applied along the propagation axis of the atomic beam uses the dipole force to concentrate the atoms in a area with a size as little as 0,4 mm while keeping the properties of low temperature of the atomic beam. With this kind of source, it is possible to create a charged-particle beam with a current greater than 1 nA. A new process of ionisation based Rydberg ionisation is studied in this thesis and compared to the early experiments based on photoionisation of cold atoms from a 3D-MOT.

In this research, Fresnel zone plates were studied using an accurate, full-electromagnetic simulator based on the body-of-revolution finite-difference time-domain (BOR-FDTD) method. This tool was used to investigate zone plates for two different applications: zone plates used as antennas in communication systems and zone plates used as focusing elements in free-space, focused-beam measurement systems. Through detailed studies of zone plates for these applications, a number of general characteristics of the zone plate were given a more in-depth look than they have been given in the past. For the first application, parametric studies were performed for Soret, folded, and grooved-dielectric, phase-correcting zone plates for antenna applications. These studies were used to generate new design graphs, from which general observations are made about the effect of varying different parameters on the focusing ability of a zone plate. For the grooved-dielectric, phase-correcting zone plate, these studies show that a number of factors influence the focusing ability in ways that are unexpected, based on many of the simple techniques typically used to analyze zone plates. Each of these factors is evaluated individually. For the second application, a zone plate was designed to be used as a focusing element in a free-space, focused-beam measurement system. To determine the suitability of zone plates for this application, simulations and measurements of the electric field were used to compare this zone plate to a doubly-hyperbolic lens. A complete focused-beam system, using two zone plates as focusing elements, was used to measure the permittivity of different dielectric materials. These measurements are compared to results for a system that uses doubly-hyperbolic lenses and to published values. A technique for increasing the usable bandwidth of a zone plate in a focused-beam system was proposed and tested. Finally, as a topic for future research, the question is posed: Using the BOR-FDTD method, can a similar volume of material be shaped in a way that results in improved focusing performance compared to a traditional zone plate? Some insight into this open-ended question can be gained by examining preliminary results of the optimization of zone plates using of a genetic algorithm.

In this work, the solubility of butyl paraben in 7 pure solvents and in 5 different ethanol-water mixtures has been determined from 1 ˚C to 50 ˚C. The solubility of ethyl paraben and propyl paraben in various solvents has been determined at 10 ˚C. The molar solubility of butyl paraben in pure solvents and its thermodynamic properties, measured by Differential Scanning Calorimetry, have been used to estimate the activity of the pure solid phase, and solution activity coefficients. More than 5000 nucleation experiments of ethyl paraben, propyl paraben and butyl paraben in ethyl acetate, acetone, methanol, ethanol, propanol and 70%, 90% ethanol aqueous solution have been performed. The induction time of each paraben has been determined at three different supersaturation levels in various solvents. The wide variation in induction time reveals the stochastic nature of nucleation. The solid-liquid interfacial energy, free energy of nucleation, nuclei critical radius and pre-exponential factor of parabens in these solvents have been determined according to the classical nucleation theory, and different methods of evaluation are compared. The interfacial energy of parabens in these solvents tends to increase with decreasing mole fraction solubility but the correlation is not very strong. The influence of solvent on nucleation of each paraben and nucleation behavior of parabens in each solvent is discussed. There is a trend in the data that the higher the boiling point of the solvent and the higher the melting point of the solute, the more difficult is the nucleation. This observation is paralleled by the fact that a metastable polymorph has a lower interfacial energy than the stable form, and that a solid compound with a higher melting point appears to have a higher solid-melt and solid-aqueous solution interfacial energy. It has been found that when a paraben is added to aqueous solutions with a certain proportion of ethanol, the solution separates into two immiscible liquid phases in equilibrium. The top layer is water-rich and the bottom layer is paraben-rich. The area in the ternary phase diagram of the liquid-liquid-phase separation region increases with increasing temperature. The area of the liquid-liquid-phase separation region decreases from butyl paraben, propyl paraben to ethyl paraben at the constant temperature. Cooling crystallization of solutions of different proportions of butyl paraben, water and ethanol have been carried out and recorded using the Focused Beam Reflectance Method, Particle Vision and Measurement, and in-situ Infrared Spectroscopy. The FBRM and IR curves and the PVM photos track the appearance of liquid-liquid phase separation and crystallization. The results suggest that the liquid-liquid phase separation has a negative influence on the crystal size distribution. The work illustrates how Process Analytical Technology (PAT) can be used to increase the understanding of complex crystallizations. By cooling crystallization of butyl paraben under conditions of liquid-liquid-phase separation, crystals consisting of a porous layer in between two solid layers have been produced. The outer layers are transparent and compact while the middle layer is full of pores. The thickness of the porous layer can reach more than half of the whole crystal. These sandwich crystals contain only one polymorph as determined by Confocal Raman Microscopy and single crystal X-Ray Diffraction. However, the middle layer material melts at lower temperature than outer layer material. / <p>QC 20130515</p> / investigate nucleation and crystallization of drug-like organic molecules