Narducci, O; (2013) Particle Engineering via Sonocrystallization: The Aqueous Adipic Acid System. Doctoral thesis , UCL (University College London).

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Abstract

Many of the companies involved in powder processing are seeking to improve their economic performance via improved control of the physical properties of their products. Pharmaceutical manufacturers, for example, are considering the potential benefits of moving from batch to continuous operations to improve consistency. Furthermore, in recent years interest in the application of ultrasound to crystallization has received a significant impetus with the increased requirement to prepare complex chemical entities to very exacting standards. Literature reports about sonocrystallization indicate several interesting benefits, including superior crystal habit, purer and easily handled product, narrowed crystal size distribution, and prolific nucleation. The sonocrystallization literature, however, mainly focuses on batch crystallization operations, with less information relating to continuous crystallization processes. The present thesis concerns an evaluation of the use of ultrasonic technology during batch and continuous crystallization of adipic acid crystals and compares it with common industrial operations for product particle engineering. Firstly, the effect of a continuous sonication on a continuous crystallization process has been investigated. Cooling crystallization of adipic acid from aqueous solution is the selected case study. Analogous experiments have been carried out both under silent and continuous insonation regimes in order to investigate the effects of sonication on the time required to reach the steady state, particle size distribution (PSD), solids yield, and crystal habit. The results reveal that under continuous ultrasonic irradiation the steady state particle size distribution is achieved after shorter times than in silent continuous crystallization experiments. Continuous crystallization with ultrasonic irradiation results in significantly smaller crystal sizes, reduced agglomeration and an improved habit of crystals with highly reproducible product characteristics. Furthermore, the product yield is increased. The crystallization kinetics, focused on both the nucleation and growth rates, has been determined using the continuous Mixed-Suspension Mixed-Product-Removal (MSMPR) crystallizer model. Kinetics have been extracted sequentially from experimental data relating the particle size distribution, using the Population Balance Equation (PBE) in terms of moments, and evaluating the effect of mean residence time, supersaturation at steady state and ultrasonic power amplitude on the growth and nucleation rates. Application of ultrasound resulted in the most pronounced effects on the nucleation process, with rates increased by one order of magnitude with the results without sonication. The Mydlarz and Jones three parameters (MJ3) model for size dependent growth fits the non-linearity in the insonated experimental population density data for crystal sizes up to 10 μm. For larger sizes, whereas the population density plot is linear, the growth rate is deemed to be independent of crystal size. Further analysis of the kinetics of nucleation and growth at steady state, in continuous crystallization under continuous insonation, has been developed using the commercially available software package PARSIVAL based on the fully adaptive Galerkin h-p method. The population balance has been modeled with secondary nucleation and a growth rate depending on both supersaturation and particle size, according to the MJ3 model. Numerically derived results from the population balance modelled with PARSIVAL are in reasonable agreement with experimental observations, in terms of population density values. The use of ultrasound in the particle engineering of micron scale adipic acid crystals has been implemented by evaluating its size reducing power compared with the product of industrially established milling processes. Specifically, the steady state particles characteristics of a continuous operation under ultrasonic irradiation and the final product characteristics of batch cooling crystallization under continuous ultrasonic have been compared with hammer milling, micronization, and High Shear Wet Milling (HSWM). Ultrasound applied to batch and continuous crystallization produces particle sizes comparable with those from micronization. Continuous insonation during batch crystallization provides spherical particles, with regular surface roughness and highly reproducible results. The use of ultrasound in the crystal product engineering has been addressed to the achievement of large particles by generating seeds crystals in-situ by means of controlled primary nucleation; the results were compared with the product of conventionally seeded crystallization. Seeded batch cooling crystallization of adipic acid from aqueous solution has been investigated to determine the effects of the method used to produce seeds and optimize seeding load, cooling rate, initial concentration, and supersaturation at seeding to achieve large particle sizes and mono-modal crystal size distribution. Finally, the analysis of final particle size distributions and particle surface characteristics has demonstrated that seed crystals generated in-situ by ultrasound offer advantages comparable with conventionally inoculated seeds, eliminating the need of previous preparation and selection of seeds and the drawbacks associated with seed handling and selection of a suitable inoculation time.

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