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    Production of inhaler grade lactose by crystallization : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Process Engineering at Massey University
    (Massey University, 2013) Shaffer, Konrad Raimund
    This work focused on producing Inhaler grade lactose (IGL) directly by crystallization. IGL is a high purity lactose excipient meeting a range of precise particle size distribution specifications. The 50 percent particle size (d50) on a volume basis desired for this work was in the range of 50 to 90 μm, and a span less than 1. IGL is commonly used as a drug carrier in dry particle inhalers. Typical industrial lactose crystallization produces lactose with a d50 greater than 200 μm and a span of around 2. The large span has been attributed to successive nucleation events during the growth phase and growth rate dispersion. Costly additional processing is currently required to produce IGL, generally in the form of sieving and milling. Initially the crystallization literature was reviewed with a specific focus on alternative methods for producing a narrow particle size distribution. From this, three methods were mathematically modelled for their ability to produce IGL. Crystallization in droplets literature and model predictions showed great potential for targeting a particle size distribution with a very low span directly from crystallization; however issues arose with scalability and potential contamination if not using a lactose or water carrier phase. Subsequent crystallization product stream processing via a hydrocyclone or inclined settler also showed the ability, in theory, to produce IGL; however both these methods were deemed as additional processing and a novel crystallization process was desired. This led to the development of the continuous settling crystallizer (CSC). The CSC consists of a vertical column, where a pre-nucleated feed stream enters near the bottom of the column and flows out the top, all under laminar conditions. Inside the column only growth occurs as additional nucleation is limited by the chosen column conditions. The CSC incorporates the key elements revealed from the literature for achieving a narrow span of a single nucleation event and a method to counteract growth rate dispersion. Slow growing crystals travel further up the column than fast growing crystals before growing to the terminal particle settling diameter, opposing flow, and settling out from the column and into the product stream. For a particular fluid velocity, the crystals settle out into the product stream at the same final particle size. Under laminar flow conditions a parabolic profile occurs across the column radius and the CSC theoretical model developed predicted a product d50 of 73 μm and a span of 0.47 for the chosen column conditions. Lab scale experiments were then carried out for the CSC. The resulting product d50 was in the desired range of 50 to 90 μm, but the span ranged from 1.4 to 1.5. Column channelling, an area of high flow and subsequent low flow elsewhere, was suspected as the cause of the experimental deviations. The theoretical model was modified to include channelling and predictions matched the experimental product results well. Due to the high level of control required for the CSC it is recommended that a batch process is designed to efficiently produce IGL; this would incorporate a single nucleation event and a hydrocyclone cut.
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    Amorphous lactose crystallisation kinetics : a thesis presented in partial fulfilment of the requirements for the degree of Master of Engineering in Bioprocess Engineering at Massey University, Manawatu, New Zealand
    (Massey University, 2012) Clark, Zachary
    The crystallisation kinetics of amorphous lactose were investigated at different relative humidity and temperature combinations. Relative humidity was controlled by placing the amorphous lactose in sealed pans containing saturated salt solutions. These pans were stored, for defined time periods, at temperatures ranging from 10-40°C above the glass transition temperature (Tg). The degree to which crystallisation had occurred was measured using both dynamic vapour sorption and isothermal microcalorimetry. The results showed crystallisation to be an all or nothing event, such that a direct measurement of the kinetics could not be obtained. This is not well accounted for by Avrami type models. It is proposed that the rapid crystallisation could be an autocatalytic effect as moisture is released during crystallisation, or a showering event as is seen in highly supersaturated lactose solutions. The latter is supported by the observation that experiments using Supertab (a blend of crystalline and amorphous lactose) show crystallisation at lower Tg conditions than is required for the crystallisation of 100% amorphous lactose. As part of confirming the equilibrium time for amorphous lactose particles the diffusion rates were investigated. The diffusivity of water through lactose was estimated by fitting a model to the DVS results. Diffusivities of 3.4 · 10-13, 1.4 · 10-14, 7.6· 10-12 and 3.6 · 10-13 m2s-1 were found for Supertab, spray dried, freeze dried and milled lactose, respectively.
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    Evaporative crystallization of alpha-lactose monohydrate : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemical Engineering at Massey University, Manawatu, New Zealand.
    (Massey University, 2012) Agrawal, Shailesh Ghanashyam
    Evaporative crystallization has been used by Fonterra Cooperative Group (New Zealand) for producing lactose. It represents an important step during lactose manufacturing where control over crystal size can be obtained, a critical parameter governing the yield and end use. The art of operating these crystallizers has been developed by observation and not from scientific principles. This project was undertaken to understand the mechanisms controlling the crystal size in evaporative crystallizers. A review of the existing literature showed that secondary nucleation is the major source of nuclei in industrial crystallizers. Based on the review, attrition, contact and fluid shear induced nucleation were identified as the probable secondary nucleation mechanisms in the studied system. Experimental investigation on each of the three mechanisms was carried out separately on a laboratory scale. It was found that the crystal size had the most significant effect on attrition, followed by impeller speed, which together implies that the crystal collision energy intensity is the dominant factor producing new fragments. Contact nucleation was also found to be controlled by crystal-impeller collisions. It was found that at the studied supersaturation there exists a minimum kinetic energy of contact below which secondary nucleation would not occur. This threshold value was used as the basis to assess the contribution of various mechanisms at the industrial scale. Shear nucleation was found to be independent of shear above 5000 s-1. A mathematical model describing the operation of the industrial crystallizer was formulated. Sensitivity analysis was conducted by simulating the model for a range of operational and kinetic parameter values. It was found that the crystal size is affected most by secondary nucleation. The volume weighted mean size approximately halved with a 5.5 times increase in the secondary nucleation rate. The model was refined to accommodate size dependent growth rate and growth rate dispersion. The kinetic parameters were fitted to match the measured size distribution from the industrial crystallizer. A range of simulations were conducted for various theoretical and empirical models and compared to that of plant measurements. Based on the results it was proposed that the majority of secondary nucleation is expected to occur in the pump and the boiling zone.
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    Characterisation of the conserved protein IMPACT from yeast (Yih1) : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry at Massey University, Manawatu, New Zealand
    (Massey University, 2012) Burr, Natalie Sarah
    Regulation of translation under conditions of amino acid starvation is an important survival mechanism to ensure the continued viability of an organism. The accumulation of uncharged tRNA under amino acid starvation conditions triggers the activation of Gcn2, a kinase that phosphorylates the translation initiation factor eIF2a, inhibiting translation initiation. The protein IMPACT has been shown to inhibit Gcn2 by sequestering Gcn1, a protein that binds Gcn2 and is required for its function in vivo. IMPACT is a highly conserved protein, but despite its conservation, little is known about the role(s) it plays in the cell. The initial aim of this study was to investigate the three dimensional structure of Yeast IMPACT Homologue 1 (Yih1) using X-ray diffraction, in the hope that knowledge of the structure would inform further understanding of its many and varied complex biological functions. Because of the difficulties in obtaining diffraction quality crystals, a number of different techniques were employed that resulted in the production of a number of different plasmids for protein expression. These included surface entropy engineering, the use of folding and stability tags, and co-crystallisation with known binding partners. Further investigation into why the protein refused to crystallise revealed an innate heterogeneity that included a propensity to bind nucleic acids. Efforts were made to determine if this was related to function without success.