Development and Scale up of High-Yield Crystallization Processes of Lysozyme and Lipase Using Additives

2013 ◽  
Vol 13 (6) ◽  
pp. 2499-2506 ◽  
Author(s):  
Dirk Hebel ◽  
Mark Ürdingen ◽  
Dariusch Hekmat ◽  
Dirk Weuster-Botz
Keyword(s):  
Scale Up ◽  
High Yield

scholarly journals Multistep batch-flow hybrid synthesis of a terbinafine precursor

2021 ◽  
Author(s):  
Tamás Hergert ◽  
Béla Mátravölgyi ◽  
Róbert Örkényi ◽  
János Éles ◽  
Ferenc Faigl
Keyword(s):  
Methyl Ether ◽  
Lithium Salt ◽  
Scale Up ◽  
Hybrid Process ◽  
High Yield ◽  
Grignard Reaction ◽  
Efficient Synthesis ◽  
Synthetic Process ◽  
Synthesis Route ◽  
Selective Addition

AbstractA three-step batch-flow hybrid process has been developed for an expeditious synthesis of the enynol key intermediate of antifungal terbinafine. This procedure involves consecutive organometallic steps without the necessity of any in-line purification: after a metalation by n-butyllithium, a selective addition of the lithium salt was elaborated followed by a Grignard reaction resulting in a high yield of 6,6-dimethylhept-1-en-4-yn-3-ol. Moreover, as an alternative to tetrahydrofuran, cyclopentyl methyl ether was used as solvent implementing a safe, sustainable, yet selective synthetic process. Even on a laboratory-scale, the optimized batch-flow hybrid process had a theoretical throughput of 41 g/h. Furthermore, the newly developed process provides an efficient synthesis route to the key-intermediate, while making acrolein obsolete, minimizing side-products, and enabling safe and convenient scale-up.

scholarly journals Synthesis of deoxymannojirimycin using a Ruthenium-catalysed hydrogen borrowing reaction

2021 ◽  
Author(s):  
◽  
Victoria Skinner
Keyword(s):  
Scale Up ◽  
Ruthenium Catalyst ◽  
High Yield ◽  
One Pot ◽  
Unfolded Protein ◽  
Unit Operations ◽  
Hepatocarcinoma Cells ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Reaction Vessels

<p>1-Deoxymannojirimycin (DMJ) has been investigated as a potential anti-cancer therapy due to its specific inhibition of class I α-mannosidase enzymes, which has been shown to trigger ER stress and the Unfolded Protein Response (UPR) pathway, leading to apoptosis in human hepatocarcinoma cells. Current methods for the synthesis of DMJ consist of multiple steps and often result in poor yields. The objectives of this research project were to develop a scale-up suitable synthesis of deoxymannojirimycin (DMJ), and to assess the feasibility of telescoping key-reactions to reduce the number of unit operations. Synthetic efforts focused on the key conversion of 1 to 2 have previously involved separate oxidation and reduction steps. In our laboratory; attempts to use hydrogen-borrowing chemistry had taken >48hr and not been achieved in high yield. The highlights of this work were that this conversion was ultimately realised in 95% yield in 24hr, and that the final deprotection of (2) could be telescoped into the process removing reaction-workup and chromatographic steps. The ruthenium catalyst used in the hydrogen borrowing reaction was found to be extremely air-sensitive, with reactions taking place in carefully prepared reaction vessels under an atmosphere of dry argon gas. The catalyst was also found to exhibit sensitivities to materials such as metal needles and polymer tubing, preventing sampling and monitoring of the reaction during synthesis. This study demonstrated that a one-pot synthesis is feasible,compressing the final steps in the synthesis of DMJ in excellent yield. The difficulty arises from the sensitive nature of the ruthenium catalyst, and the extreme care required in the preparation of the glassware and reagents used in synthesis. Many aspects of this development require further investigation, including the sampling, monitoring and quality control of each synthetic step.</p>

scholarly journals Synthesis of deoxymannojirimycin using a Ruthenium-catalysed hydrogen borrowing reaction

2021 ◽  
Author(s):  
◽  
Victoria Skinner
Keyword(s):  
Scale Up ◽  
Ruthenium Catalyst ◽  
High Yield ◽  
One Pot ◽  
Unfolded Protein ◽  
Unit Operations ◽  
Hepatocarcinoma Cells ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Reaction Vessels

<p>1-Deoxymannojirimycin (DMJ) has been investigated as a potential anti-cancer therapy due to its specific inhibition of class I α-mannosidase enzymes, which has been shown to trigger ER stress and the Unfolded Protein Response (UPR) pathway, leading to apoptosis in human hepatocarcinoma cells. Current methods for the synthesis of DMJ consist of multiple steps and often result in poor yields. The objectives of this research project were to develop a scale-up suitable synthesis of deoxymannojirimycin (DMJ), and to assess the feasibility of telescoping key-reactions to reduce the number of unit operations. Synthetic efforts focused on the key conversion of 1 to 2 have previously involved separate oxidation and reduction steps. In our laboratory; attempts to use hydrogen-borrowing chemistry had taken >48hr and not been achieved in high yield. The highlights of this work were that this conversion was ultimately realised in 95% yield in 24hr, and that the final deprotection of (2) could be telescoped into the process removing reaction-workup and chromatographic steps. The ruthenium catalyst used in the hydrogen borrowing reaction was found to be extremely air-sensitive, with reactions taking place in carefully prepared reaction vessels under an atmosphere of dry argon gas. The catalyst was also found to exhibit sensitivities to materials such as metal needles and polymer tubing, preventing sampling and monitoring of the reaction during synthesis. This study demonstrated that a one-pot synthesis is feasible,compressing the final steps in the synthesis of DMJ in excellent yield. The difficulty arises from the sensitive nature of the ruthenium catalyst, and the extreme care required in the preparation of the glassware and reagents used in synthesis. Many aspects of this development require further investigation, including the sampling, monitoring and quality control of each synthetic step.</p>

scholarly journals Pushing Nanomaterials past the Kilogram Scale—a Targeted Approach Integrating Scalable Microreactors, Machine Learning and High-Throughput Analysis

2020 ◽  
Author(s):  
Nicholas Jose ◽  
mikhail Kovalev ◽  
Eric Bradford ◽  
Artur Schweidtmann ◽  
Hua Chun Zeng ◽  
...  
Keyword(s):  
Machine Learning ◽  
High Throughput ◽  
Scale Up ◽  
Process Efficiency ◽  
High Yield ◽  
Synthesis Methods ◽  
High Throughput Analysis ◽  
Throughput Analysis ◽  
Highly Active ◽  
Technological Advances

Novel materials are the backbone of major technological advances. However, the development and wide-scale introduction of new materials, such as nanomaterials, is limited by three main factors—the expense of experiments, inefficiency of synthesis methods and complexity of scale-up. Reaching the kilogram scale is a hurdle that takes years of effort for many nanomaterials. We introduce an improved methodology for materials development, combining state-of-the-art techniques—multi-objective machine learning optimization, high yield microreactors and high throughput analysis. We demonstrate this approach by efficiently developing a kg per day reaction process for highly active antibacterial ZnO nanoparticles. The proposed method has the potential to significantly reduce experimental costs, increase process efficiency and enhance material performance, which culminate to form a new pathway for materials discovery.

scholarly journals Oriented Fermentation of Food Waste towards High-Value Products: A Review

Energies ◽  
2020 ◽  
Vol 13 (21) ◽  
pp. 5638
Author(s):  
Qiao Wang ◽  
Huan Li ◽  
Kai Feng ◽  
Jianguo Liu
Keyword(s):  
Lactic Acid ◽  
Food Waste ◽  
Volatile Fatty Acids ◽  
High Efficiency ◽  
Continuous Fermentation ◽  
Scale Up ◽  
High Yield ◽  
Organic Loading Rate ◽  
Market Demand ◽  
Acid Fermentation

Food waste has a great potential for resource recovery due to its huge yield and high organic content. Oriented fermentation is a promising method with strong application prospects due to high efficiency, strong robustness, and high-value products. Different fermentation types lead to different products, which can be shifted by adjusting fermentation conditions such as inoculum, pH, oxidation-reduction potential (ORP), organic loading rate (OLR), and nutrients. Compared with other types, lactic acid fermentation has the lowest reliance on artificial intervention. Lactic acid and volatile fatty acids are the common products, and high yield and high purity are the main targets of food waste fermentation. In addition to operational parameters, reactors and processes should be paid more attention to for industrial application. Currently, continuously stirred tank reactors and one-stage processes are used principally for scale-up continuous fermentation of food waste. Electro-fermentation and iron-based or carbon-based additives can improve food waste fermentation, but their mechanisms and application need further investigation. After fermentation, the recovery of target products is a key problem due to the lack of green and economic methods. Precipitation, distillation, extraction, adsorption, and membrane separation can be considered, but the recovery step is still the most expensive in the entire treatment chain. It is expected to develop more efficient fermentation processes and recovery strategies based on food waste composition and market demand.

scholarly journals Engineering of a Highly Efficient Escherichia coli Strain for Mevalonate Fermentation through Chromosomal Integration

2016 ◽  
Vol 82 (24) ◽  
pp. 7176-7184 ◽  
Author(s):  
Jilong Wang ◽  
Suthamat Niyompanich ◽  
Yi-Shu Tai ◽  
Jingyu Wang ◽  
Wenqin Bai ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Shake Flask ◽  
Mevalonate Pathway ◽  
High Titer ◽  
Scale Up ◽  
Coli Strain ◽  
High Yield ◽  
Glycolytic Flux ◽  
Chromosomal Integration ◽  
Theoretical Yield

ABSTRACTChromosomal integration of heterologous metabolic pathways is optimal for industrially relevant fermentation, as plasmid-based fermentation causes extra metabolic burden and genetic instabilities. In this work, chromosomal integration was adapted for the production of mevalonate, which can be readily converted into β-methyl-δ-valerolactone, a monomer for the production of mechanically tunable polyesters. The mevalonate pathway, driven by a constitutive promoter, was integrated into the chromosome ofEscherichia colito replace the native fermentation geneadhEorldhA. The engineered strains (CMEV-1 and CMEV-2) did not require inducer or antibiotic and showed slightly higher maximal productivities (0.38 to ∼0.43 g/liter/h) and yields (67.8 to ∼71.4% of the maximum theoretical yield) than those of the plasmid-based fermentation. Since the glycolysis pathway is the first module for mevalonate synthesis,atpFHdeletion was employed to improve the glycolytic rate and the production rate of mevalonate. Shake flask fermentation results showed that the deletion ofatpFHin CMEV-1 resulted in a 2.1-fold increase in the maximum productivity. Furthermore, enhancement of the downstream pathway by integrating two copies of the mevalonate pathway genes into the chromosome further improved the mevalonate yield. Finally, our fed-batch fermentation showed that, with deletion of theatpFHandsucAgenes and integration of two copies of the mevalonate pathway genes into the chromosome, the engineered strain CMEV-7 exhibited both high maximal productivity (∼1.01 g/liter/h) and high yield (86.1% of the maximum theoretical yield, 30 g/liter mevalonate from 61 g/liter glucose after 48 h in a shake flask).IMPORTANCEMetabolic engineering has succeeded in producing various chemicals. However, few of these chemicals are commercially competitive with the conventional petroleum-derived materials. In this work, chromosomal integration of the heterologous pathway and subsequent optimization strategies ensure stable and efficient (i.e., high-titer, high-yield, and high-productivity) production of mevalonate, which demonstrates the potential for scale-up fermentation. Among the optimization strategies, we demonstrated that enhancement of the glycolytic flux significantly improved the productivity. This result provides an example of how to tune the carbon flux for the optimal production of exogenous chemicals.

scholarly journals Obtaining Antioxidants and Natural Preservatives from Food By-Products through Fermentation: A Review

Fermentation ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. 106
Author(s):  
Francisco J. Martí-Quijal ◽  
Sucheta Khubber ◽  
Fabienne Remize ◽  
Igor Tomasevic ◽  
Elena Roselló-Soto ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Current Knowledge ◽  
Scale Up ◽  
Added Value ◽  
High Yield ◽  
Future Research ◽  
Antioxidant Compounds ◽  
Antioxidant Peptides ◽  
Natural Preservatives ◽  
By Products

Industrial food waste has potential for generating income from high-added-value compounds through fermentation. Solid-state fermentation is promising to obtain a high yield of bioactive compounds while requiring less water for the microorganism’s growth. A number of scientific studies evinced an increase in flavonoids or phenolics from fruit or vegetable waste and bioactive peptides from cereal processing residues and whey, a major waste of the dairy industry. Livestock, fish, or shellfish processing by-products (skin, viscera, fish scales, seabass colon, shrimp waste) also has the possibility of generating antioxidant peptides, hydrolysates, or compounds through fermentation. These bioactive compounds (phenolics, flavonoids, or antioxidant peptides) resulting from bacterial or fungal fermentation are also capable of inhibiting the growth of commonly occurring food spoilage fungi and can be used as natural preservatives. Despite the significant release or enhancement of antioxidant compounds through by-products fermentation, the surface areas of large-scale bioreactors and flow patterns act as constraints in designing a scale-up process for improved efficiency. An in-process purification method can also be the most significant contributing factor for raising the overall cost. Therefore, future research in modelling scale-up design can contribute towards mitigating the discard of high-added-value generating residues. Therefore, in this review, the current knowledge on the use of fermentation to obtain bioactive compounds from food by-products, emphasizing their use as natural preservatives, was evaluated.

scholarly journals Optimization of Vapor Diffusion Conditions for Anti-CD20 Crystallization and Scale-Up to Meso Batch

Crystals ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 230 ◽  
Author(s):  
Huaiyu Yang ◽  
Benny Danilo Belviso ◽  
Xiaoyu Li ◽  
Wenqian Chen ◽  
Teresa Fina Mastropietro ◽  
...  
Keyword(s):  
Concentrate Solution ◽  
Scale Up ◽  
Crystal Form ◽  
Storage Conditions ◽  
High Yield ◽  
Major Step ◽  
Vapor Diffusion ◽  
Therapeutic Uses ◽  
Anti Cd20 ◽  
Cluster Of Differentiation

The crystal form is one of the preferred formulations for biotherapeutics, especially thanks to its ability to ensure high stability of the active ingredient. In addition, crystallization allows the recovery of a very pure drug, thus facilitating the manufacturing process. However, in many cases, crystallization is not trivial, and other formulations, such as the concentrate solution, represent the only choice. This is the case of anti-cluster of differentiation 20 (anti-CD20), which is one of the most sold antibodies for therapeutic uses. Here, we propose a set of optimized crystallization conditions for producing anti-CD20 needle-shaped crystals within 24 h in a very reproducible manner with high yield. High crystallization yield was obtained with high reproducibility using both hanging drop vapor diffusion and meso batch, which is a major step forward toward further scaling up the crystallization of anti-CD20. The influence of anti-CD20 storage conditions and the effect of different ions on the crystallization processes were also assessed. The crystal quality and the high yield allowed the first crystallographic investigation on anti-CD20, which positively confirmed the presence of the antibody in the crystals.

scholarly journals Utilization of By-Product of Groundnut Oil Processing for Production of Prodigiosin by Microbial Fermentation and Its Novel Potent Anti-Nematodes Effect

Agronomy ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 41
Author(s):  
Thi Hanh Nguyen ◽  
San-Lang Wang ◽  
Manh Dung Doan ◽  
Thi Huyen Nguyen ◽  
Thi Ha Trang Tran ◽  
...  
Keyword(s):  
Potential Application ◽  
Low Cost ◽  
Scale Up ◽  
Cost Effective ◽  
Black Pepper ◽  
High Yield ◽  
Small Scale ◽  
Groundnut Oil ◽  
Egg Hatching ◽  
Oil Processing

This study aimed to reuse groundnut oil processing by-product, groundnut cake (GNC) for the low-cost production of prodigiosin (PG) via microbial technology and to assess its novel potential application for the management of black pepper nematodes. Serratia marcescens TUN02 was found as the most active PG-producing strain. Various small-scale experiments conducted in flasks indicated that GNC at 1% may be used as the sole carbon/nitrogen source for cost-effective PG production by fermentation. Notably, no further commercial ingredients and salts are required to supplement into the culture medium of this fermentation. PG was further investigated for scale-up production in a 14-L bioreactor system and PG was produced at high yield (6886 mg/L) with large-scale volume (4 L) in a short cultivation time (10 h). PG was then purified and its nematicidal activity was evaluated and showed effective inhibition of juveniles and egg hatching of Meloidogyne incognita species, harmful on black pepper, with low IC50 values of 0.2 and 0.32 mg/mL, respectively. The simple medium containing 1% GNC is the first report of cost-effective biosynthesis of PG, as well as potential in vitro anti-egg hatching activity of PG. These results indicated the potential application of GNC for low-cost bioproduction of PG for promising and novel use in the management of black pepper nematodes.

scholarly journals Robust Agrobacterium-Mediated Transient Expression in Two Duckweed Species (Lemnaceae) Directed by Non-replicating, Replicating, and Cell-to-Cell Spreading Vectors

2021 ◽  
Vol 9 ◽  
Author(s):  
Anton Peterson ◽  
Olena Kishchenko ◽  
Yuzhen Zhou ◽  
Maksym Vasylenko ◽  
Anatoli Giritch ◽  
...  
Keyword(s):  
Transient Expression ◽  
Potato Virus ◽  
Mammalian Cells ◽  
Fluorescent Protein ◽  
Scale Up ◽  
Potato Virus X ◽  
High Yield ◽  
Protein Accumulation ◽  
Expression Systems ◽  
Potato Leaf

Plant-based transient expression systems have recognized potential for use as rapid and cost-effective alternatives to expression systems based on bacteria, yeast, insect, or mammalian cells. The free-floating aquatic plants of the Lemnaceae family (duckweed) have compact architecture and can be vegetatively propagated on low-cost nutrient solutions in aseptic conditions. These features provide an economically feasible opportunity for duckweed-based production of high-value products via transient expression of recombinant products in fully contained, controlled, aseptic and bio-safe conditions in accordance with the requirements for pharmaceutical manufacturing and environmental biosafety. Here, we demonstrated Agrobacterium-mediated high-yield transient expression of a reporter green fluorescent protein using deconstructed vectors based on potato virus X and sweet potato leaf curl virus, as well as conventional binary vectors, in two representatives of the Lemnaceae (Spirodela polyrhiza and Landoltia punctata). Aseptically cultivated duckweed populations yielded reporter protein accumulation of &gt;1 mg/g fresh biomass, when the protein was expressed from a deconstructed potato virus X-based vector, which is capable of replication and cell-to-cell movement of the replicons in duckweed. The expression efficiency demonstrated here places duckweed among the most efficient host organisms for plant-based transient expression systems, with the additional benefits of easy scale-up and full containment.

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