Model-based solvent selection for pharmaceutical process development

Solvents play a key role in the manufacturing of pharmaceutical products as they are extensively used to accelerate synthetic reactions, enable separation and purification, and facilitate drug product formulation. The production of active pharmaceutical ingredients (APIs) is a multi-step process involving several reaction and workup steps in which large amounts of solvents are consumed. This makes the pharmaceutical industry a very wasteful chemical sector and highlights the need for systematic tools to enhance the resource efficiency of its processes. Recently, there has been growing interest in incorporating green chemistry principles in product design and development to enhance the sustainability of chemical manufacturing. In particular, solvent selection is a promising research area within the chemistry and engineering communities, given the many solvent-related contributions to process performance, including mass utilisation, energy consumption and process economics. Solvent selection is a difficult and complex design problem that entails molecular-level decisions, such as determining the solvent identities and the compositions of mixtures if mixed solvents are considered, together with process performance objectives, which are often competing. In current practice, most pharmaceutical companies develop in-house solvent selection guides to choose solvents based on physico-chemical properties and safety, health and environment characteristics with the aim to reduce process costs and environmental impact. However, these methods are mostly based on heuristic approaches or time-consuming experimental investigations that often lead to sub-optimal designs and fail to account for the integrated nature of the solvent selection problem. A novel solvent selection approach based on computer-aided mixture/blend design (CAMbD) is proposed to design integrated pharmaceutical processes and evaluate the process performance of pharmaceutical synthesis routes. Predictive thermodynamic models are used to integrate property prediction within process modelling, and advanced optimisation techniques are employed to search the vast design space of potential solvents and process conditions in order to identify the most promising design options. The CAMbD approach is used to optimise the solvent identities, mixture composition and process conditions in: 1) integrated synthesis and crystallisation processes, and 2) end-to-end drug substance manufacturing processes, based on key performance indicators (KPIs) that quantify resource efficiency and product quality. The one-step synthesis of mefenamic acid from 2,3-dimethylaniline and 2-chlorobenzoic acid is used as a case study to illustrate the use of CAMbD in pharmaceutical process design. The CAMbD approach generates different designs by considering a variety of solvent design spaces and performance objectives. Furthermore, multi-objective optimisation CAMbD problems are formulated to explore the trade-offs between competing KPIs, such as solvent utilisation and process safety, or energy consumption and process yield, in order to identify best-compromise solutions. An important feature of the proposed approach is that comprehensive design specifications, such as the miscibility of the chosen reaction and crystallisation solvents with the wash solvent in the end-to-end process, can be embedded in the mathematical formulation, ensuring that only practical designs are obtained. In addition to its use in integrated molecular and process design, the proposed CAMbD approach can be deployed to identify the optimal synthesis route of a pharmaceutical compound based on process performance metrics quantifying resource efficiency, product quality and solvent cost. The two-step synthesis of 4-nitrophenol (NP) via two reaction pathways is used as a case study to illustrate the potential of CAMbD in pharmaceutical process route selection. The work presented in this thesis constitutes a unique scientific contribution to the area of model-based solvent selection for drug substance manufacturing. For the first time, a CAMbD-based approach is developed and deployed to identify promising solvent choices and operating conditions for integrated, end-to-end drug substance manufacturing processes, while focusing on mixture thermodynamics, i.e., species solubility, and considering a range of KPIs that quantify product and process performance within single and multi-objective design formulations. Furthermore, for the first time, CAMbD is deployed to evaluate synthesis routes based on process performance, i.e., process route evaluation, while using simplified thermodynamic models and considering process-related metrics such as process efficiency and product quality. The model-based tool presented in this PhD thesis is relevant to streamline experiments and guide solvent selection and process design during early-stage pharmaceutical process development.Open Acces

Reactivity of Dimethylplatinum (II) Complexes

This thesis describes a study of dimethylplatinum(II) and dimethylplatinum(IV) complexes containing bidentate nitrogen donor ligands. This work deals with oxidative addition, and reductive elimination chemistry, and it focuses on synthesis, characterization, and reaction mechanisms in studies of these complexes. The compound [PtMe2(bpe)], bpe = 1,2-bis(2-pyridyl)ethane, is easily oxidized to give octahedral organoplatinum(IV) complexes and the subsequent chemistry is profoundly influenced by the accompanying strain induced in the 7-membered Pt(bpe) chelate ring. On reaction of [PtMe2(bpe)] with HCl, the initial product [PtHClMe2(bpe)] undergoes reductive elimination of methane to form [PtClMe(bpe)]. In contrast, methyl iodide reacts with [PtMe2(bpe)] to give [PtIMe3(bpe)], and this decomposes by loss of the bpe ligand to give the cubane [(PtIMe3)4] and not by reductive elimination. Finally, a new class of platinum(IV) double cubane clusters was obtained on oxidation of complex [PtMe2(bpe)] with either hydrogen peroxide to give [Pt4(m-OH)4(m3-OH)2Me10], as a mixed complex with [PtMe2(CO3)(bpe)], or with oxygen in methanol to give [Pt4(m-OH)2(m-OMe)2(m3-OMe)2Me10]. The oxidation of the complex [PtMe2(bps)], bps = bis(2-pyridyl)-dimethylsilane, by oxygen, hydrogen peroxide or dibenzoyl peroxide in the presence of water or alcohol gives the complex cation, [PtMe3(k3-N,N,O-HOSiMe(2-C5H4N)2)]+, in a reaction involving easy cleavage of a methylsilicon bond. Treatment of the complex [PtMe2(bps)] with B(C6F5)3 in trifluoroethanol in air gives the complex [Me(bps)Pt-OSiMe(2-C5H4N)2PtMe3]+ [B(OCH2CF3)(C6F5)3]-. The unique binuclear platinum complex is formed via the competitive methyl platinum group cleavage from [PtMe2(bps)] by the acid H[B(OCH2CF3)(C6F5)3] to give the platinum(II) fragment and oxidation by air to give the platinum(IV) fragment. Combination of the two units then gives the binuclear complex which involves a very easy methylsilicon group cleavage reaction. The platinum(II) complexes containing five-membered heterocyclic imidazole ligands show high reactivity to a broad variety of alkyl halides, peroxides, and halogens forming stable platinum(IV) complexes. The dimethylplatinum(II) complex [PtMe2{(mim)2C=CH2}], (mim)2C=CH2= 1,1-bis(1-methylimidazole-2-yl)ethene reacts with dichloromethane to give the dimethylplatinum(IV) complex [PtCl(CH2Cl)Me2{(mim)2C=CH2}]. The product exists as a mixture of two isomers, the cis isomer as the kinetic product and the trans isomer as the thermodynamic product. The dimethylplatinum(II) complex [PtMe2(DECBP)], DECBP = 4,4’-diethoxycarbonyl-2-2’-bipyridine], undergoes easy oxidative addition to the corresponding platinum(IV) complexes. The reactions of the complex [PtMe2(DECBP)] with alkyl bromides RCH2Br, which have hydrogen bond donor or acceptor functional groups, result in the formation of stable platinum(IV) complexes. Those complexes self-assemble in the solid state to form supramolecular polymers via the intermolecular OH•••O=C, N-H•••Br, OH•••BrPt, interactions, with other predicted interactions such as the π-stacking, and the C(H)•••BrPt secondary weak interactions

Nutritional Profile and Medicinal Properties of Pumpkin Fruit Pulp

Having high nutritional value and low cultivation costs, pumpkin fruit makes a great candidate to be used by the food industry as a functional ingredient. To prolong its shelf life and widen the array of its potential uses in food products, drying and powdering have been applied, producing pumpkin flour. Several studies have been done to optimize the drying method of pumpkin in order to preserve or reduce the loss of its nutritional constituents and color changes during drying and storage. As vacuum freeze drying produces great quality pumpkin powder and best preserves the β-carotene and phenolic contents of the fruit, it is considered an expensive technique that could be inconvenient to be used in developing countries or for cost-reduction purposes. Air drying is a cheaper technique but results in less nutrient preservation than vacuum drying. This highlights the role of pretreatments in order to reduce the loss of nutrients and produce better quality pumpkin flour. Hot water blanching followed by metabisulfite pretreatment results in the best carotenoid stability and preservation of phenolic compounds in the produced powder. Incorporation of pumpkin powder in wheat bread could increase its nutritional value by increasing the levels of dietary fiber, pro-vitamin A β-carotene, calcium, iron, and zinc and by decreasing the carbohydrate and caloric contents

Future of the Lebanese Middle School Science Teaching Methods: The Importance of Teacher’s Shifting from Passive Learning to More Active Learning in Science Classes

This study evaluated the importance of integrating active learning techniques in to Lebanese middle school science classes. It examined the effect of this modification on students' academic performance and social development .The researcher collected data by using mixed method approach referred to as sequential explanatory design where the research collected both quantitative and qualitative data. The quantitative data was collected by distributing questionnaire developed based on 5 point Likert- scale to a non-probability convenience sample (N=50) of science teachers and the qualitative data was collected by performing an online interview with four middle school science teachers. The researcher used Statistical Package for the social sciences program (SPSS) to analyze quantitative data and to answer the studied hypothesis and problematic by using three tests (a) one sample T-test, (b) one way Manova test, and (c) correlation test. The interview data was analyzed qualitatively .The findings of this study showed that (a) there is a significant importance for teachers’ shifting from passive learning to more active learning in Lebanese middle school science classes, (b) Lebanese middle school science teachers are modifying their teaching methods in their classes to improve students' academic performance and social development, and (c) there is a significant effect of the teaching methods modification on students' academic performance and social development based on the Lebanese middle school teachers' perspective

Disabled Friendly Facility between Feasibility and Legality

Most hotels in Lebanon, built before 2011, do not provide access to disabled persons in light of 220/2000 law. This is due to: 1/ a misconception that a Disabled Friendly Facility (DFF) would be on behalf of hotel guests’ satisfaction and consequently, would reduce hotel’s popularity and revenue; 2/ a fear that the unforeseen demand for DFFs will be offset by expenses and, in best-case scenarios, would not generate enough profits to pay back initial investments. In brief, hotel-business investors are not sure about the convenience of a DFF and about the number of DFFs to provide in light of 7194/2011law. The objective of this paper is, on the first hand, to demonstrate the financial feasibility and the economic convenience of a DFF and, on the other hand, to test its impact on the satisfaction of hotel guests. In other terms, on the popularity of the hotel

Surface Defect Detection Using YOLO Network

Detecting defects on surfaces such as steel can be a challenging task because defects have complex and unique features. These defects happen in many production lines and differ between each one of these production lines. In order to detect these defects, the You Only Look Once (YOLO) detector which uses a Convolutional Neural Network (CNN), is used and received only minor modifications. YOLO is trained and tested on a dataset containing six kinds of defects to achieve accurate detection and classification. The network can also obtain the coordinates of the detected bounding boxes, giving the size and location of the detected defects. Since manual defect detection is expensive, labor-intensive and inefficient, this paper contributes to the sophistication and improvement of manufacturing processes. This system can be installed on chipsets and deployed to a factory line to greatly improve quality control and be part of smart internet of things (IoT) based factories in the future. YOLO achieves a respectable 70.66% mean average precision (mAP) despite the small dataset and minor modifications to the network

Influence of Psycho-social Support on Stakeholder Engagement in Lebanon’s School Community

Psycho-social Support (PSS) is a practical approach to improve people's well-being affected by humanitarian crises. However, empirical research on how it can improve engagement within academic settings is still limited. To address this gap, the current study investigates the impact of the PSS Program in improving the stakeholders' engagement within the school community in Lebanon by implementing counseling and supportive activities or services. The study selected a mixed research design and a cross-sectional survey to answer the research questions and to test the hypotheses. In April 2021, a sample of 446 respondents was selected from among the school stakeholders in Lebanon using the convenience and purposive sampling techniques. Data collected was coded, cleaned, and entered into Statistical Package for Social Sciences (SPSS) for analysis. The study confirmed that PSS significantly influences stakeholder engagement that lead into stakeholder belongingness, and quality and equity of education. Based on the outcomes, the researcher recommended adopting the PSS program to better the quality of education and assist administrations with more details that improve stakeholder engagement in their schools. The study also shows best practices in the utilization of the PSS to inspire stakeholder engagement during emergencies. Findings are necessary to the ministry of education, school administrators, students, parents, and researchers interested in using PSS in school settings

Bone metastatic prostate cancer and resistance to tyrosine kinase inhibitors: an intimate relationship between loss of miR-203 and up-regulation of EGFR signaling

A tumor suppressor role for miR-203 in RAS-dependent prostate cancer metastasis has been described recently by our group. We have explored the regulatory mechanisms by which miR-203 is being regulated through EGFR signaling. We investigated the molecular mechanism of metastasis and identified novel roles of genes that interact with miR-203 downstream of activated Ras. We showed an amplifying regulatory loop involving the direct interaction of miR-203 with the EGFR ligands, AREG, EREG, and TGFA 3’UTR. Using clinical specimens and database analysis, our data suggested that decreasing miR-203 and increasing EGFR ligands, AREG, EREG, and TGFA expressions are correlated with prostate cancer progression. Since tyrosine kinase inhibitors (TKIs) have been shown to inhibit tyrosine phosphorylation of EGFR in a dose-dependent manner, we examined a role for miR-203 in TKIs-induced apoptosis in RAS-activated prostate cancer. We investigated the mechanisms by which miR-203 overexpression contributes to TKIs-resistant RAS-activated prostate cancer cells apoptosis. We have shown indications for candidate miR-203 targets that are either influenced by anti-apoptotic proteins (e.g. API5, BIRC2, and TRIAP1) or positively influenced by a novel NF-κB-inducible oncogenic molecule, TNFAIP8. These observations suggest that the latter category may be synergistically affected by the regulatory loop of miR-203 depletion and anti-apoptotic proteins overexpression. Our results provided evidence showing a role of miR-203 in regulating the expression of EGFR signaling genes in response to TKIs-resistance during prostate cancer progression

Employee Engagement: A Lebanese Bank Contextual Understanding

The Lebanese banking industry has played a fundamental role in the Lebanese economy over the years. However, since 2011, Lebanese banks have started to face many challenges and changes due to globalisation, competition, and many other factors, leading to a major employee retention problem. Thus, the need to create a healthy and engaged workplace environment has recently started to gain the attention of most organisations in Lebanon. Yet to date, only a limited number of studies addressing employee engagement as a tool have been done in Lebanon. Therefore, the main purpose of this study is to understand and analytically investigate the relevance of the concept of engagement in the Lebanese context. The second aim is to propose a functional managerial best practice model that might be useful to the LB Bank