Controlling crystal size distribution (CSD) is important to downstream processing and to product quality. It is well-recognized that selective removal functions can be used to influence CSD, for example by manufacturing a product with a larger dominant size or narrower distribution. Early work on the use of feedback control to manipulate the residence time distribution functions of fines in a continuous crystallizer demonstrated the utility of such an approach in handling process upsets and cycling that resulted from system instability. These efforts were extended to batch crystallization, although there remained significant difficulty associated with on-line analysis of the size distribution. The development of new technologies, such as Focused Beam Reflectance Measurement (FBRM), provides a methodology for on-line monitoring of a representation of the crystal population in either batch or continuous crystallization systems. The FBRM technology is based on laser light scattering; properly installed, it allows on-line determination of the chord length distribution (CLD), which is statistically related to the CSD and depends on the geometry of the crystal. The purpose of the present study is to use the FBRM to monitor the evolution of CSD characteristics and to implement a feedback control scheme that provides the flexibility to move the CSD in a preferred direction. Cooling batch crystallizations of paracetamol has been chosen to investigate implementation of the control scheme. The work will show how fines removal and varying cooling rates provide reliable and practical control of crystal size distribution.

Les hydrates de gaz sont des composés solides formés à partir de molécules de gaz emprisonnées dans des structures cristallines formées par des molécules d'eau reliées par liaisons hydrogène. Ils sont stables sous des conditions de haute pression et de basse température. Dans les conduites pétrolières, la formation d'hydrate de gaz peut être responsable du colmatage des conduites et du blocage des vannes. Pour éviter leur cristallisation, il existe plusieurs solutions : l'isolation ou le réchauffage de la conduite pétrolière ainsi que l'injection d'additifs cinétiques ou thermodynamiques. Une autre solution envisagée est l'utilisation d'additifs anti-agglomérants. Il s'agit d'agents tensio-actifs qui favorisent d'abord la formation d'une émulsion eau dans huile et ensuite limitent l'agglomération entre les cristaux une fois formés. De cette façon, la taille des particules d'hydrates serait limitée par la taille des gouttelettes d'eau dans l'émulsion. Cette méthode a été utilisée dans les travaux de Camargo (2001) à l'IFP et puis de Fidel-Dufour (2004) à l'ENSM de Saint-Etienne. Cette thèse est une étude consacrée à la caractérisation du couplage entre la cristallisation des hydrates et la rhéologie des écoulements pétroliers diphasiques (émulsion eau dans huile) laminaires ou turbulents dont l'objectif final est la production d'un modèle de cristallisation en écoulement. Elle s'appuie sur les mesures réalisées à l'aide de la sonde FBRM (Focused Beam Reflectance Measurement) qui permet des mesures en longueurs de cordes (CLD) in-situ lors de la formation d'hydrates en systèmes dispersés. La formation des hydrates de gaz en écoulement est étudiée de manière expérimentale sur deux dispositifs : une boucle de circulation Archimède située à l'ENSM-SE et une boucle de circulation Lyre à l'IFP Lyon. Les résultats obtenus avec les deux dispositifs sont comparés. La plus grande partie de ce travail a porté sur l'interprétation des mesures de longueurs de corde de la FBRM. Une série d'algorithmes permettant de générer des agrégats aléatoires ont été élaborés, suivis du calcul de leurs CLD. Ces CLD sont comparées avec les CLD obtenues expérimentalement permettant ainsi le suivi de l'agglomération pendant la cristallisation en écoulement.

Methane hydrate formation and dissociation studies from high water content (>60 vol% water) – crude oil emulsions were performed. The hydrate and emulsion system was characterized using two particle size analyzers and conductivity measurements. It was observed that hydrate formation and dissociation from water-in-oil (W/O) emulsions destabilized the emulsion, with the final emulsion formulation favoring a water continuous state following re-emulsification. Hence, following dissociation, the W/O emulsion formed a multiple o/W/O emulsion (60 vol% water) or inverted at even higher water cuts, forming an oil-in-water (O/W) emulsion (68 vol% water). In contrast, hydrate formation and dissociation from O/W emulsions (≥71 vol% water) stabilized the O/W emulsion.

An understanding of the mechanism for hydrate formation from water-in-oil emulsions is integral for progressing from preventing hydrate formation through expensive thermodynamic means to hydrate blockage prevention. This work presents hydrate formation and agglomeration in a stirred system studied using two complementary particle size analysis techniques, a Particle Video Microscope (PVM) and a Focused Beam Reflectance Measurement (FBRM). The PVM provides qualitative visual information through digital images in the black oil illuminated by a series of lasers. The FBRM provides a quantitative chord length distribution of the particles/droplets in the system. Three sets of experiments were performed using two different Crude oils, Conroe with a very small asphaltene content and poor emulsion stability, and Caratinga with a much higher asphaltene content and emulsion stability. The first experiments looked at ice as an analogy to hydrates, studying the morphology with both the PVM and FBRM. The second experiments looked at the effect of droplet size on hydrate formation and agglomeration, and the third set of experiments studied the dissociation process using a combination of the PVM and in situ conductivity measurements to determine the continuous phase. For hydrate formation, droplet size was found to have a major effect on whether or not agglomeration will occur. During dissociation agglomeration is extremely dramatic due to the creation of surface water on the particles. The dissociation of these agglomerates results in a significant destabilization of the suspension into a water/hydrate phase at the bottom of the cell until dissociation is complete. The dissociation conceptual picture presented illustrates an important implication when operating a flow line with hydrates present; dissociation within the pipeline should be prevented until the hydrates are out of the flow line.

Batch crystallization is used widely in the production of high-value added species. It is widely recognized that product properties, some of which may be related directly to the utility of the drug, and downstream processes, such as tableting, are influenced by crystal morphology, size, and shape. The ability to observe on-line the evolution of the population density and detect a polymorphic transformation would constitute a major asset in understanding crystallizer operation and the phenomena that influence product quality. Focused-beam reflectance measurement (FBRM) is among the process analytical technologies (PAT) that hold promise for enhanced monitoring of pharmaceutical crystallization. It is based on scattering of laser light and provides a methodology for on-line monitoring of a representation of the crystal population in either batch or continuous crystallization systems. Properly installed, the FBRM allows on-line determination of the chord-length density, which is a complex function of crystal geometry and is statistically related to the population density. A model based on the geometry of the crystal was therefore established to relate both densities and thus enable computation of the population density from a measured chord length density. The evolution of the population density as a function of time leads to the estimation of the supersaturation and therefore allows the determination of the systems kinetics. From there, the population balance can be solved. Paracetamol is a common substance which exhibit polymorphism and is mainly used as an analgesic and antipyretic drug. The developed model was here applied to batch cooling crystallization of paracetamol from ethanol solutions; this system was used to explore the utility of FBRM data in detection of the polymorphic transformations. As different shapes generate different chord length densities, a transition from one polymorphic form with one specific crystal habit to another can be tracked through the FBRM. The purpose of the present study is to use the FBRM to monitor the evolution of the crystallization process, develop a model describing the evolution of the process, and monitor polymorphic transformation. The end results would be the possibility to implement a better control of the crystallization process that would ensure that downstream processing and product quality meet expectations.

The LignoBoost process is a valuable supplement to the Kraft process. It can increase the pulp production rate of a Kraft mill and it enables lignin separation from black liquor with a high degree of purity. However, residual xylan in black liquor has been observed to increase filtration resistance of lignin during the LignoBoost process. In order to uncover underlying mechanisms, this thesis investigates the potential influence of xylan during lignin precipitation and filtration, which are the two main steps of the LignoBoost process. For this purpose experiments based on a model system were designed. Model liquors consisted of lignin and xylan as the only organic compounds and contained lower salt concentrations (4.2-5.9 wt%) compared to black liquor. Furthermore, reference liquors were prepared without xylan addition. Precipitation mechanisms were studied in the onset precipitation region (i.e. alkaline regime) by in-situ focused beam reflectance measurements (FBRM) during step-by-step acidic precipitation of the model liquor. It was found that the onset precipitation pH does not change with the presence of xylan as all liquors started precipitation around pH 9.15. The filtration process was investigated on model liquors that had been precipitated by fast acidification to acidic regimes (pH 6.5-2.87). The use of FBRM during acid precipitation of model liquors suggested that temperature had a significant influence on the chord length distribution (CLD) of the particles. In all filtration experiments, a decrease in CLD was observed when the temperature was changed from 80 °C to 25 °C. Moreover, this thermal instability of particles seemed to be higher when added xylan was present in the liquor. The investigation of the resulting filer cakes with HPLC showed that xylan was evenly distributed through the cake. Further findings on the influence of xylan were impeded due to variations in ionic strength in the model liquors. It was found that the effect of ionic strength on filtration properties and particle sizes overshadows the effect of xylan. Higher ionic strength was observed to yield a lower filtration resistance, a higher solidosty, larger particles and lower solid surface area, as investigated by filtration measurements, laser diffraction and BET analysis. Finally, xylan was fluorescently tagged (i.e. dyed) with Remazol Brilliant Blue R to investigate xylan position in the ligninxylan filer cake, using a confocal fluorescence microscope. However, due to the autofluorescence of lignin as well as low emission intensity of the synthesized dyed xylan, xylan could not been tracked within the lignin particle. Nevertheless, valuable insight was gained into the preparation of dyed xylan and the bond stability.

The research addressed in this thesis focuses on monitoring and characterization of pharmaceutical compounds by laser backscattering. In particular, this study covers two topics: (1) the determination of naproxen sodium solubility in water, and its phase transition; and (2) comparisons of batch and laminar flow tubular crystallizers for the production of paracetamol (acetaminophen) and D-mannitol. Using a Lasentec™ Focused Beam Reflectance Measurement (FBRM) device, the solubility of naproxen sodium in aqueous solutions was determined over a temperature range from 15.2 to 39.7 ℃ With the determination of the solubilities of two pseudopolymorphs, anhydrous and dihydrated naproxen sodium, the phase transition point between these two forms of the pharmaceutical compound was determined to occur at 30.3 ℃ Enthalpy of solution and metastable zone widths were also determined for the experimental conditions. Crystallizations of paracetamol and D-mannitol were performed in a batch crystallizer and in a laminar flow tubular crystallizer (LFTC) system. In the latter system, supersaturation was generated rapidly in the solution being transported through a temperature-controlled tube and recovered in a batch vessel where product crystals were grown to equilibration. Because of the rapid rate at which supersaturation was generated in the LFTC, the resulting crystals were of smaller mean size than those obtained from batch crystallizations. The total time required for crystallization was significantly less with the LFTC than with the batch unit. Additionally, the rapid cooling in the LFTC led to the formation of two different polymorphs of paracetamol, Forms I and II.

Active pharmaceutical ingredients (APIs) are frequently delivered to the patient in the solid-state as part of an approved dosage form (tablets, capsules, etc.). Understanding and controlling the solid-state chemistry of APIs is therefore an important aspect of the drug development process. APIs can exist in a variety of distinct solid forms, including polymorphs, solvates, hydrates, co-crystals and amorphous solids. Each form displays unique physicochemical properties that can profoundly influence the bioavailability, manufacturability, stability and other performance characteristics of the drug. Most APIs are purified and isolated by crystallisation from an appropriate solvent during the final step in synthetic process. The main objective of a crystallisation process is to produce crystals with desired properties such as particle size distribution (PSD), shape and purity. All pharmaceutical dosage forms must be produced in uniform units, and good content of uniformity is only possible when the size of the active component is carefully controlled. For on-line control of crystallisations of Quetiapine Fumarate to achieve desired PSD and no changed physicochemical purity was used the Lasentec Focus Beam Reflectance Measurement (FBRM) system.