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The pharmaceutical industry has traditionally implemented batch manufacturing for the production of a wide range of products due to its mature technological development and ability for recall of products where necessary. However, several demonstrations of Continuous Pharmaceutical Manufacturing (CPM) in the past two decades have drawn significant attention from academia, industry and regulatory bodies due to its potential for smaller equipment, enhanced efficiencies, access to difficult or hazardous process conditions with greater ease and safety and reduced costs and waste. While continuous processing is not new in other manufacturing sectors, its application to pharmaceutical production has only drawn significant attention in recent years due to the numerous demonstrations of continuous flow syntheses of complex molecules and functional groups inherent of Active Pharmaceutical Ingredients (APIs), which is the foundation of any end-to-end CPM plant. The literature to date has predominantly focussed on design and optimisation of flow synthesis routes; however, the development of efficient continuous separation processes is a major bottleneck to CPM and are often challenging and materially intensive unit operations. The design of effective continuous separation processes for societally important APIs amenable to continuous production is essential for CPM success. Mathematical modelling is a viable and useful tool in the elucidation of promising designs prior to pilot plant studies that can allow rapid screening of multiple candidate configurations and can circumvent expensive and laborious experimental campaigns. Moreover, they allow optimisation of process design configurations to maximise their operational and economic benefits. This PhD thesis aims to elucidate cost-optimal upstream CPM plant and continuous separation process designs for a range of APIs. Steady-state process models for upstream CPM plants for different APIs are constructed, using published data for reaction rate law elucidation and kinetic parameter estimation, activity coefficient and group contribution models for non-ideal multicomponent mixture phase equilibria prediction and pharmaceutical process costing methodologies. The constructed models are then used for process simulation, design and optimisation of CPM plants, using Nonlinear Programming (NLP) for individual case-based process optimisation and Mixed Integer Nonlinear Programming (MINLP) for CPM process synthesis to optimality. The systematic frameworks and methods used in this work can be expanded to other APIs amenable to CPM with similar processes. This work highlights the immense value in systematic and rigorous model-based simulation and optimisation campaigns for CPM process development.

Butanol is a promising biofuel which can be manufactured by fermentation. Irrespective of whether n-butanol or iso-butanol is produced, the alcohol is generally expressed at low concentrations (~1 wt%) in these fermentations. It also inhibits the organisms, and so removal of the butanol from the fermentation vessel as it is produced can improve the productivity of the fermentation. However, separation of dilute butanol from aqueous fermentation broths requires substantial amounts of energy. In this dissertation, a novel separation technique has been devised, employing the solvent extraction of butanol from aqueous broths by volatile hydrocarbons. This separation technique performs the separation of butanol selectively and efficiently. It is investigated theoretically in this dissertation. The use of volatile hydrocarbons allows the extracted butanol and the hydrocarbon to be separated by distillation, employing waste heat from the fermenter or other similar lowgrade heat sources. Such heat is often abundant on fermentation plants. Therefore, minimal high-grade heat (heat at temperatures higher than the fermenter) would be required for the process. The equilibria of butanol and side-products with C4 - C5 hydrocarbons were investigated using vapour-liquid equilibria and excess enthalpy measurements from the literature. Models of the extraction and distillation processes were then built using these analyses. A flowsheet simulation predicted that under 2 MJ/kg butanol of high-grade heat (mostly at only ~50°C) was required by the separation scheme provided that sufficient low-grade waste heat was available (~40 - 20 MJ/kg butanol for extraction of 1 - 2 wt% broths). This high-grade heat requirement is around 5% of the heat required for distillation of butanol from aqueous broths at 1 wt% Various configurations of flowsheet and solvent were investigated to improve the process. Distribution coefficients of butanol in C4 - C6 hydrocarbons were found to triple between 37°C and 100°C, and therefore extraction performed at elevated temperatures was found to significantly reduce the low-grade heat requirements of the system. The formation of butanol-gasoline blends via extraction of butanol into volatile hydrocarbons could also eliminate high-grade heat requirements.

Heightened concerns for cleaner air and increasingly more stringent regulations on sulphur content in transportation fuels will make desulphurization more and more important. The sulphur problem is becoming more serious in general, particularly for diesel fuels as the regulated sulphur content is getting an order of magnitude lower, while the sulphur contents of crude oils are becoming higher. This thesis aimed to develop a desulphurisation process (based on oxidation followed by extraction) with high efficiency, selectivity and minimum energy consumption leading to minimum environmental impact via laboratory batch experiments, mathematical modelling and optimisation. Deep desulphurization of model sulphur compounds (di-n-butyl sulphide, dimethyl sulfoxide and dibenzothiophene) and heavy gas oils (HGO) derived from Libyan crude oil were conducted. A series of batch experiments were carried out using a small reactor operating at various temperatures (40-100 °C) with hydrogen peroxide (H2O2) as oxidant and formic acid (HCOOH) as catalyst. Kinetic models for the oxidation process are then developed based on 'total sulphur approach'. Extraction of unoxidised and oxidised gas oils was also investigated using methanol, dimethylformamide (DMF) and N-methyl pyrolidone (NMP) as solvents. For each solvent, the 'measures' such as: the partition coefficient (KP), effectiveness factor (Kf) and extractor factor (Ef) are used to select the best/effective solvent and to find the effective heavy gas oil/solvent ratios. A CSTR model is then developed for the process for evaluating viability of the large scale operation. It is noted that while the energy consumption and recovery issues could be ignored for batch experiments these could not be ignored for large scale operation. Large amount of heating is necessary even to carry out the reaction at 30-40 °C, the recovery of which is very important for maximising the profitability of operation and also to minimise environmental impact by reducing net CO2 release. Here the heat integration of the oxidation process is considered to recover most of the external energy input. However, this leads to putting a number of heat exchangers in the oxidation process requiring capital investment. Optimisation problem is formulated using gPROMS modelling tool to optimise some of the design and operating parameters (such as reaction temperature, residence time and splitter ratio) of integrated process while minimising an objective function which is a coupled function of capital and operating costs involving design and operating parameters. Two cases are studied: where (i) HGO and catalyst are fed as one feed stream and (ii) HGO and catalyst are treated as two feed streams. A liquid-liquid extraction model is then developed for the extraction of sulphur compounds from the oxidised heavy gas oil. With the experimentally determined KP multi stage liquid-liquid extraction process is modelled using gPROMS software and the process is simulated for three different solvents at different oil/solvent ratios to select the best solvent, and to obtain the best heavy gas oil to solvent ratio and number of extraction stages to reduce the sulphur content to less than 10 ppm. Finally, an integrated oxidation and extraction steps of ODS process is developed based on the batch experiments and modelling. The recovery of oxidant, catalyst and solvent are considered and preliminary economic analysis for the integrated ODS process is presented.

Fresh water in Kuwait is produced by non- conventional methods. About 95% of this water comes from desalinated seawater using multi-stage flash distillation technique and the remainder comes from underground brackish water. The blended water containes organic, inorganic and trace metal impurities within the recommended international standard limits. The purpose of this work is to identify the source of selected trace metals present in the drinking water in Kuwait. Chromium, copper, iron, lead, manganese, nickel, vanadium and zinc have been analysed using atomic absorption spectroscopy (AAS) and inductively coupled plasma mass spectroscopy (ICPMS). Efforts were made to improve the preconcentration of the selected metals and their separation from the high concentration of salts in seawater which affect the accuracy and cause major interference in the analysis. Solid-liquid extraction (chelex-100 resin) and liquid-liquid extraction (methyl iso-butyl ketone and freon) with and without back-extraction into nitric acid were investigated. Liquid-liquid extraction without back-extraction proved to give optimum recovery of the selected metals. Results confirmed that both AAS and ICP-MS are suitable for the analysis of trace metals in Kuwait's waters. Although AAS technique proved to be more accurate in analysing the selected metals than ICP-MS, the latter was adopted since its accuracy is acceptable (1.1-4.4%) and it is easier and faster than the former technique. The study revealed that the source of copper, iron, nickel and zinc is the construction materials of the distillation plants, while the source of lead and vanadium is the brackish water. Manganese and chromium concentrations are very low in all sources. No direct relationship between the metal concentration in the seawater and the distillate could be deduced.

Liquid-liquid extraction (LLE) is one of the most common and widely utilized separation techniques in industrial processes to date, with countless industrial systems employing this unit operation around the world. Although LLE offers an easy and low-energy methodology for separating miscible liquids, its design is necessarily constrained by the need to avoid the formation of emulsions. Emulsions, while very effective in helping an extraction process reach its thermodynamic equilibrium, are difficult to separate out, often rendering the entire LLE system economically unviable. As such, LLE operations typically avoid emulsion formation and instead opt for non-emulsified systems that typically have lower extraction efficiencies and correspondingly higher operating costs. In the production of volatile fatty acids (VFAs) from fermentation broth, for example, the separation block can be responsible for up to half of the overall process cost. Alternatives to LLE, such as distillation or electrodialysis, struggle with similar tradeoffs related to high economic or environmental costs. The ideal miscible liquid separation system should be highly energy-efficient, possess low operating costs, easily scalable, and compatible with existing industrial processes. In this dissertation, we describe how our recently developed membrane-based LLE process termed as Continuous Liquid-liquid Extraction And iN-situ Separation (CLEANS) operates at high efficiency with reduced operating costs and minimal energy input. We examine the recovery of volatile fatty acids (VFAs) and ammonia via CLEANS, and make note of our separation technology’s unique strengths. This dissertation begins by addressing one of the most ubiquitous challenges faced by any membrane-based process—surface fouling. We show that our optimized hydrophilic and oleophobic (HL/OP) membranes are capable of rapidly separating emulsions many times faster than by gravity alone, and that they can function even after over a month of continuous fouling in oil. Next, we design a CLEANS based LLE process using these HL/OP membranes. Our optimized CLEANS process demonstrates a capacity to recover VFAs over an order of magnitude more efficiently than has been reported previously. We then study the scale up and techno-economics of the developed CLEANS system for VFA extraction. Our work illustrates that the CLEANS process enables highly consistent extraction efficiency across variable scales of operation, as well as significantly lower operating costs and shorter payback periods when compared with traditional LLE operations. Finally, we expand the utility of our CLEANS processes by demonstrating its effectiveness in converting dissolved ammonia found in wastewater directly into ammonium sulfate, a product that is widely utilized as a fertilizer. We highlight our CLEANS process’ unique advantages for this particular application—namely, that it does not require heating of the feed stream, nor the addition of costly or environmentally detrimental chemicals. Overall, this dissertation aims to demonstrate the utility of the CLEANS process to act as an effective recovery methodology for a wide variety of industrially relevant chemical species. We anticipate that the CLEANS process may prove beneficial for separation across a diverse set of industries including bio-processing, fuel purification, wastewater treatment, chemical synthesis, and many more.

A study of the extraction of cobalt II ions from an aqueous growing drop into a continuous medium of di-2-ethylhexylphosphoric acid (D2EHPA) is made. The apparatus for this technique is described and a flow injection analysis method for measuring the cobalt remaining in the aqueous phase has been developed. In this study the feed concentration of cobalt has varied between 8.48 x 10-3 and 16.97 x 10-3 mole 9-1. The D2EHPA held in n-heptane, has been altered between 0.143 and 2.41 mole P. Also, pH has been adjusted between 3.10 and 4.44. The principal temperature applied to this study was 25 ±0.5*C. Acetate buffers have been used, but it is shown by calculation that about 70% of the cobaltous ion is in an uncomplexed form. The kinetics of the extraction have been modelled using a method based upon reaction in an aqueous zone near to the liquid-liquid interface with diffusion of species towards and away from the interface. This model provided a fundamental parameter 01 which incorporates the chemical rate constant kR, the D2EHPA partition coefficient PHR, the acid dissociation constnat KD for D2EHPA and the metal ion diffusivity in the interface diffusion region. The results have been compared with those of other workers who studied the transfer of cobalt into an organic drop from an aqueous continuum. The diffusion controlling film is the aqueous one. The rate constant for, the extraction reaction equation is, from this work, kR - 106.34 M3 kmol-1 sec-1 which can be compared with that found by another worker using the reverse transfer system, i. e. kR - 106.18 m3 kmol-I sec-i. . Finally, the mass transfer coefficients were found to change with varying feed concentrations and pH, this is also in agreement with other workers who have studied different liquid-liquid systems.

The production of plastic and the amount of waste plastic that enters the environment increases every year. Synthetic polymers will gradually break down into particles on the micro- and nano-scale. The micro- and nano-plastics pose a significant ecological harm by transporting toxic chemicals and causing inflammation and cellular damage when ingested. Two common plastics are polyethylene terephthalate (PET) and Polystyrene (PS), and a newer bioplastic polylactic acid (PLA) that has become a popular alternative. Deep eutectic solvents are a recently discovered solvent composed of a hydrogen bond donor and hydrogen bond acceptor and have been proposed as a cheaper alternative to ionic liquids. Hydrophobic varieties of natural DES (NADES) have been used as extractants in liquid-liquid extractions. The aim of this study is to investigate the relationship between three NADES and micro- and nano-plastics in a liquid-liquid extraction system. The results show that all three NADES extracted plastic particles in the range of 55%-83% with varying rates of extraction. The conclusions from this study are that the plastic particles have a higher affinity for NADES than water and may extract at different rates, but the maximum percentage of plastic particles extracted does not vary significantly.

A cannabinoid refers to any natural or synthetic compound that interacts with the CB1 and CB2 receptors. There are currently three different groups of cannabinoids: endogenous cannabinoids, phytocannabinoids and synthetic cannabinoids. The most common phytocannabinoid is delta-9-tetrahydrocannabinol (THC), which is the active component in the Cannabis sativa or marihuana plant1–3. Two examples of synthetic cannabinoids that are present in case reports from 2012 to 2018 are AB-FUBINACA and AB-PINACA4–7. THC and synthetic cannabinoids are commonly encountered drugs in forensic toxicology cases, therefore, being able to extract these compounds and their metabolites is imperative for toxicological interpretation. There are a variety of commercially available sample preparation techniques for these analytes. Companies such as UCT, Biotage, Millipore-Sigma, Tecan, and Thermo Fisher Scientific manufacture these products. The focus of this research was to evaluate these techniques for their cleanliness, efficiency and cost effectiveness. Sample preparation techniques are designed to remove the different components of the matrix and other prescription or illicit substances present in the sample that could interfere with the assay, increase the analyte recovery, extraction efficiency, decrease variability, and clean-up the sample to allow for less instrument downtime and longer column life8. This study focused on comparing a liquid-liquid extraction (LLE), solid phase extraction (SPE), and supported liquid extraction (SLE). The primary purpose of this study was to develop and validate the three above mentioned sample preparation techniques for the analysis of THC, 11-hydroxy-THC, 11-nor-9-carboxy-THC (THCCOOH), AB-FUBINACA, AB-FUBINACA metabolite 3, and AB-PINACA in blood and urine. Parameters assessed followed Academy Standards Board (ASB) Standard 036, Standard Practices for Method Validation in Forensic Toxicology, including recovery, suppression, and matrix effects. For urine and blood analysis, the calibration range was determined to be 1 ng/mL to 50 ng/mL for all three techniques. Urine recovery was highest for the LLE method, with all compounds having a recovery greater than 50%. The SLE method had the lowest LOQ results for urine, with 0.5 ng/mL for 11-hydroxy-THC and THCCOOH, 0.75 ng/mL for THC, AB-FUBINCA and AB-FUBINACA metabolite 3, and 1 ng/mL for AB-PINACA. Ion suppression was reduced using the SLE method for urine along with having the shortest sample preparation time of 1 hr for up to 48 samples. For blood analysis, the LLE method had the greatest recovery of all analytes. The LLE method also had reduced suppression and matrix effects compared to the SPE method. Sample preparation was shorter for the SPE method, consuming 2 hrs for an average sample batch, compared to 4 hrs for the LLE method, which included a 2 hr freezing step. In conclusion, for urine analysis, all three sample preparation techniques were acceptable for the analysis of THC, synthetic cannabinoids, and their metabolites, with the SLE method being the preferred method. For blood analysis a LLE and SPE method were developed and are adequate for the analysis of THC, synthetic cannabinoids, and their metabolites, with the LLE method being the preferred method.

This research study successfully completed three objectives: 1) validate liquid-liquid, supported-liquid, and solid-phase extractions for the quantitation of three barbiturates (amobarbital, butalbital, and phenobarbital) in blood and urine using liquid chromatography-tandem mass spectrometry; 2) to compare the efficiency and effectiveness among methods in accomplishing extraction of barbiturates under the laboratory setting at Boston University School of Medicine; and 3) to report all the analytical data to RTI International for interlaboratory comparison. For the validation study, a six-point linear calibration model (20-2000 ng/mL) with inversely weighted concentration (1/x) was reproducible in all three sample preparation methods for both blood and urine with r2 greater than or equal to 0.994. Bias and precision evaluated from three controls throughout the range of the curve were within ±20% and ±20%CV, respectively. Neither carryover nor interference was observed. Detection limits were evaluated down to 5 ng/mL depending on the extraction procedure. Samples were able to be diluted up to 50 times prior to instrumental analysis. Samples were stable on autosampler at room temperature up to 72 hours after their initial analysis. Recovery of barbiturates from blood and urine all ranged from 45% to 86%. The effect of ionization suppression or enhancement was found to have minimal impact on the validation. For choosing the most suitable method quantifying barbiturates, efficiency and effectiveness were studied. Efficiency evaluates the time and ease of sample preparation required to prepare a sample for analysis. Supported-liquid extraction was found to be the most efficient method for extracting barbiturates as it required the least amount of time to perform and could be easily automated with minimal training. Effectiveness is an assessment of one’s ability to selectively recover target analyte at a reasonably low concentration. By considering a method’s recovery, extract cleanliness, detection limits, and reproducibility, liquid-liquid extraction was the best at quantifying barbiturates in blood and supported-liquid extraction was the most suitable method for extracting barbiturates from urine. For interlaboratory comparison, all the data collected has been reported to RTI International. These findings can be used for examining the overall reliability and reproducibility of the validated methods. Results obtained can also be used to explore the possibility for streamlining sample preparation in the forensic laboratory, and hence reducing the case backlog.

The overuse of antibiotics in agriculture is an emerging concern, due to their potential detrimental impact to the environment. This study focuses on exploring antimicrobial properties of lignin derived compounds. Lignin is of interest as a feedstock to replacing some petroleum-based chemicals and products because it is the most abundant source of renewable aromatic compounds on the planet. Two lignin rich streams, residues from the enzymatic hydrolysis of dilute acid and alkaline pretreated corn stover, were decomposed via pyrolysis and hydrogenolysis, respectively. The resulting liquid oils were subjected to sequential extractions using a series of solvents with different polarities. Chemical compositions of the extracted fractions were characterized through HPLC and GC/MS. These extracted compounds were screened against Saccharomyces cerevisiae (S. cerevisiae), Escherichia coli, and Lactobacillus amylovorus for antimicrobial properties. Six lignin model monomers: guaiacol, vanillin, vanillic acid, syringaldehyde, 2,6-dimethoxyphenol, and syringic acid were compared to the oils and extracted fractions for antimicrobial properties. Development of lignin-derived chemicals with antimicrobial properties could provide a novel use for this underutilized natural resource.

Gangliosides are membrane lipids with a complex sugar head containing sialic acid (polar) and a ceramide moiety made up of a sphingosine and a fatty acid (non-polar). Typically, gangliosides are part of the ganglion, a group of nerve cell bodies where they act as neuroprotective agents, support, and maintenance of the mature neuronal cells. Glaucoma is an age-related neurodegenerative disorder of the eye that leads to blindness. Retinal ganglion cells (RGCs) in retinal tissue of the eye, degeneration is seen followed by the optic nerve head damage. From immunohistochemistry studies with cholera toxin-B, gangliosides which are part of the RGCs were lost during the RGCs degeneration. Non-neuronal cells, astrocytes, which do not express gangliosides in normal retinal tissue surprisingly express/uptake gangliosides in correlation to the RGCs degeneration. Astrocyte expression/uptake of gangliosides can play protective, adverse or combined effects at different times. An identification and quantitation of individual gangliosides that are expressed/uptake provide an insight into understanding the pathophysiology of glaucoma.A specific, sensitive and quantitative liquid-chromatography-mass spectrometry (LC-MS/MS) analytical techniques were developed to identify heterogeneous molecular species of gangliosides. Of all of them, new LC-MS/MS method using a phenyl-hexyl reverse-phase chromatography was successful in resolving eight major gangliosides and ten minor gangliosides. An optimized ganglioside isolation technique was developed which is a combination of liquid-liquid extraction for lipid phase separation followed by a solid-phase extraction for desalting and removal of debris. This new LC-MS/MS method was validated for linearity, repeatability, matrix effect and recovery studies. Age studies (young vs old mice) were performed for the first time to correlate the changes of gangliosides in retinal tissue level in comparison to the superior colliculus of the mid-brain using the new LC-MS/MS method in normal control mice (C57BL/6J) versus glaucoma model mice (DBA/2J). LC-MS/MS results show an increase of major gangliosides in the glaucoma retinal tissue from old to young age mice groups whereas little change in the superior colliculus. Nevertheless, these gangliosides changes were statistically insignificant as p-value is > 0.05. The optic nerve studies using electron microscopy was undertaken to establish the glaucoma disease progression. Electron microscopy study results show no change in the optic nerve count which represents no glaucoma in old age animal samples. Thus, a non-correlation was seen with the ganglioside changes compared to optic nerve counts. A greater animal sample with much older age provides a better understanding of gangliosides role in glaucoma.

The rare earth elements (REE), composed primarily of the fifteen lanthanides, find broad application in many modern devices making them indispensable and important to the sustainable, green world approach prevalent these days. Liquid-liquid extraction for the separation of lanthanides using a calix[4]arene scaffold with coordinating ligands on its lower rim has been studied for many years. New solid phase materials capable of coordinating metals are important to the field of rare earth metal separation and isolation as they will not only minimize solvent wastes but have the potential to be reused, thereby making the separation and recovery of rare earth metals economical. In the first part, the synthesis and characterization of new chlorine terminated 2-alkyl-p-tert-butylcalix[4]arenes with different coordinating ligands such as phosphine oxides, ketones, CMPO, and esters on the lower rim were investigated. Here, the extraction efficiencies of these new calix[4]arenes for rare earth metals in liquid-liquid extraction was investigated in order to confirm that functionalization at the 2-position of the calix[4]arenes does not interfere with the extraction properties of the coordinating ligands on the lower rim.In the second part of this project, further modification of the 2-position was carried out by converting the chlorine terminated end to the highly desirable amino group, which was then utilized in coupling reactions to immobilize these 2-position/tail modified calix[4]arenes bearing lower rim coordinating ligands on solid supports covalently via the attached linker group. These newly synthesized solid phase extractants were characterized using solid state NMR spectroscopy, FT-IR spectroscopy, elemental analysis and EDS and their thermal stability was further determined using TGA. This represents the first report of attachment of calix[4]arene ligands to solid supports via their 2-positions to the best of our knowledge. These new materials were further investigated in the separation of lanthanides.

Nuclear power waste contains radioactive isotopes with long half lives and the problem lies in the fact that the lanthanides and actinides must be separated before the nuclear waste can be reprocessed. Transuranic Extraction (TRUEX), a liquid-liquid extraction method, has been developed but fails to separate the lanthanide and actinides and creates large volumes of liquid waste. It has been shown that attaching three CMPO (carbamoyl phosphine oxide) ligands used in the TRUEX process to a calixarene increases the separation and extraction efficiency of the system. The research goal is to attach the CMPO ligand to a polymer to make a membrane to be used in nuclear waste remediation. The triblock polymer system has been designed to have a cross-linking group to create the membrane structure, a solubilizing group to improve the flow of aqueous media through the membrane, and the CMPO ligand to chelate actinides. This paper describes the design of the polymer, its synthesis, and my research data.