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Glycosphingolipids such as α- and β-glucosylceramides (GlcCers) and α- and β- galactosylceramides (GalCers) are stereoisomers differentially synthesized by gut bacteria and their mammalian hosts in response to environmental insult. Thus, lipidomic assessment of α- and β-GlcCers and α- and β-GalCers is crucial for inferring biological functions and biomarker discovery. However, simultaneous quantification of these stereoisomeric lipids is difficult due to their virtually identical structures. Differential mobility mass spectrometry (DMS), as an orthogonal separation to high performance liquid chromatography used in electrospray ionization, tandem mass spectrometry (LC-ESI-MS/MS), can be used to separate stereoisomeric lipids. Generating LC-ESI-DMS-MS/MS methods for lipidomic analyses is exceedingly difficult demanding intensive manual optimization of DMS parameters that depend on the availability of synthetic lipid standards. Where synthetic standards do not exist, method development is not possible. To address this challenge, I developed a supervised in silico machine learning approach to accelerate method development for ion mobility-based quantification of lipid stereoisomers. I hypothesized that supervised neural network models could be used to learn the relationships between lipid structural characteristics and optimal DMS machine parameter values thereby reducing the total number of empirical experiments required to develop a DMS method and enabling users to “predict” DMS parameters for analytes that lack synthetic standards. Specifically, this thesis describes a supervised learning approach that learns the relationship between two DMS machine parameter values (separation voltage and compensation voltage) and two lipid structural features (N-Acyl chain length and degree of unsaturation). I describe here, iDMS, an algorithm that was trained on 17 lipid species, and can further simulate results of DMS manual method development and suggest optimal parameter values for 47 lipid species. This approach promises to greatly accelerate the development of assays for the detection of lipid stereoisomers in biological samples.

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Melt granulation is a versatile process that is underutilized in the pharmaceutical industry. Most pharmaceutical wet granulation and twin-screw extruders can be adapted for melt granulation. Twin-screw melt granulation (TSMG) is of interest since is a continuous process and allows for flexible process design and a high degree of control. TSMG can be used to produce formulations for oral immediate or sustained release. This research focuses on the use of TSMG to taste-mask APIs. Many APIs are bitter or unpleasant tasting. Taste-masking may be required, particularly for products intended for pediatric patients. Taste-masking has been achieved with many different techniques, but a simple, cost-effective method that can be applied to many different APIs is not currently available. A matrix encapsulation approach using continuous twin-screw melt granulation was attempted with three different APIs. The resulting granule properties, particularly particle size, are related to the granulation process parameters. Prediction of taste-masking based on in vitro assessments is challenging and generally clinical evaluation is required. A small-volume dissolution method was developed as a screening test the melt granules. It is not clear if this technique is predictive of clinical taste-masking performance, but it is expected to be an improvement over discrete sampling or typical quality control dissolution methods. The dissolution rate was estimated using the Noyes-Whitney equation and correlated to the mean granule particle size. From this, a simple model for time to a taste threshold could be used to define a design space around the granulation process. / Pharmaceutical Sciences

Row patterns affected irrigated corn productivity when grown in the Mid-South region of the United States. Narrow (76 cm) row spacing increased grain yield 8% when compared to traditional wide (96-102 cm) row spacing. Twin rows (20-25 cm spacing) in a wide (96-102 cm) row pattern, produced similar grain yield as a traditional wide single row. At a normal plant density of 79,040 ha-1, traditional wide rows yielded 10.51 Mg ha-1, twin wide rows yielded 10.34 Mg ha-1, and the narrow rows yielded 11.33 Mg ha-1. Growing corn at various plant densities did not affect corn grain yield response to various row patterns. As a comparison the traditional wide rows and twin rows were similar in their yield, and the narrow rows performed better. Corn grain yields for the traditional 96-102 cm wide single rows were 11.20 Mg ha-1, wide 96-102 cm twin rows yielded 11.22 Mg ha-1, and narrow 76 cm rows produced 12.07 Mg ha-1. Row pattern had no effect on corn plant height, photosynthetically active radiation (PAR), leaf area index (LAI), SPAD, stalk diameter, and plant lodging in either study.

Granulation is an important process for industries ranging from plastics to food and pharmaceutics. In the last decades, the twin-screw extruder has been more and more studied as a continuous method for granulation. But there are many questions remaining to be answered such as the functions of kneading block and the granulation behavior in this zone, the influence of the wetting method, and also the influence of the active pharmaceutical ingredient (API) properties on the granulation process. Therefore, in this project, a series of experiments were performed based on a new technique to the granulation field named ‘screw pullout’ for understanding the granulation process within the twin-screw extruder. In order to understand the specific function of an important screw element known as a kneading block, the physical particle motion reflecting progress of granulation was monitored along the screw. Different feed rate and formulations were studied; the residence time and pressure in kneading block were measured; and the granules along the screw were characterized for their porosity and size distribution. It was found that granule consolidation and breakup within the kneading block allowed the production of granules with consistent properties and excellent mechanical strength. However, the changes produced by a kneading block are dependent upon the formulation. For example, the kneading block demonstrates no observable function with formulations containing a significant content of microcrystalline cellulose. The most notable benefit of the kneading block to all tested materials appeared to be distribution of the interstitial binding liquid rather than to compact the powders. A new wetting method using a foam binder has been studied intensively in this work to assess its influence on the granulation process. A series of studies have been performed to compare the granule development along the screws as powder formulation and screw design were varied to test for the differences induced by the two wetting methods (foam delivery or liquid injection). The evolution of the granules along the screw was characterized by analyzing the particles size distribution, porosity, and fracture strength. It was found that the wetting method had minor impact on the particle size distribution due to the strong mechanical dispersion inherent to the extruder. The major finding for the pharmaceutical industry was that the foam method reduces the required amount of liquid to granulate, thereby dropping drying time after the process. The foamed binder was also found to be preferred when the formulation contains powder components with poor spreading properties. Finally, the influence of an API’s physical properties on granulation was studied by comparing formulations with varying API hydrophobicity. It was found that the API and binder distribution was not affected by the hydrophilicity of API, while the particle size distribution, porosity and fracture strength were strongly dependent on the properties of the API. / Thesis / Master of Applied Science (MASc)

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Yes / It has been shown that seeded granules of calcium carbonate can be produced in commercial batch high shear granulators such as the Cyclomix high-shear impact mixer. Seeded granules are attractive to the pharmaceutical industry due to their high uniformity and good mechanical properties which can assist efficient tablet manufacture. In the current study, attempts to produce seeded granules of Durcal 65 and PEG 4000 binder using hot melt granulation are reported, in response to the recent shift towards continuous pharmaceutical manufacturing. Various screw configurations and rotation speeds were investigated in a series of experiments to determine the relationship between process conditions and granule properties. Particle size analysis, strength measurement and structural characterisation were used to quantify granule properties. It was found that using a series of kneading elements arranged at a 60° staggering angle located near to the feed section of the extruder screw generated strong, spherical granules. From structural characterisation approximately 5–15% of extruded granules were found to be seeded. Twin screw melt granulation is therefore considered to be a promising technique for continuous production of seeded granules, although a more detailed investigation is required to optimise yield and quality.

Maintenance management is a relevant issue in modern technical systems due to its financial, safety, and environmental implications. The need to rely on physical assets makes maintenance a necessary evil, which, on the other hand, allows achieving a high quality of end products, or services, and a safety level that is adequate for the regulatory requirements. The advent of the fourth industrial revolution offers meaningful opportunities to improve maintenance management; technologies such as Cyber-Physical Systems, the Internet of Things, and cloud computing enable realizing modern infrastructure to support decisions with advanced analytics. In this thesis, the optimization of maintenance policies is tackled in this renewed technological context. The research methods employed in this thesis include interviewing of subject experts, literature research, and numerical experiments. Mathematical modelling is used to model network effects in complex technical systems, and simulations are used to validate the proposed models and methodologies. The problem of maintenance policies comparison is addressed in one of the publications; using the proposed bi-objective analysis, an effective maintenance policy was identified. Maintenance of complex systems organized in a networked fashion is studied in another project, where maintenance costs and system performances are considered. The proposed model allowed to identify a set of non-dominated (in the Pareto sense) maintenance policies, and an efficient resolution procedure was developed. The possibility to use a digital twin to replicate a Cyber-Physical System for maintenance policies optimization is addressed in another publication. The main hurdles in realizing such a complex infrastructure are analyzed, and managerial implications are presented. Finally, following a qualitative research approach, the opportunities offered by additive manufacturing are identified and presented in a book chapter. The opportunities for both maintenance efficiency gains and new business models are identified and discussed.