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 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.

X-ray analysis of crystals of rat phosphatidylinositol-transfer protein with bound phosphatidylcholine

1999 ◽  
Vol 55 (2) ◽  
pp. 522-524 ◽  
Author(s):  
Randall L. Oliver ◽  
Jacqueline M. Tremblay ◽  
George M. Helmkamp ◽  
Lynwood R. Yarbrough ◽  
Natalie W. Breakfield ◽  
...  
Keyword(s):  
Crystal Form ◽  
Unit Cell ◽  
Asymmetric Unit ◽  
Unit Cell Parameters ◽  
Vapor Diffusion ◽  
Solvent Content ◽  
Cell Parameters ◽  
Transfer Protein ◽  
Phosphatidylinositol Transfer Protein ◽  
Phosphatidylinositol Transfer

Phosphatidylinositol-transfer protein (PITP) is a soluble, ubiquitously expressed, highly conserved protein encoded by two genes in humans, rodents and other mammals. A cDNA encoding the alpha isoform of the rat gene was expressed to high levels in Escherichia coli, the protein purified and the homogeneous protein used for crystallization studies. Crystals of rat PITP-α were obtained by vapor-diffusion techniques using the sitting-drop method. Crystals grow within two weeks by vapor-diffusion techniques in the presence of polyethylene glycol 4000. Both crystal forms pack in the monoclinic space group P21. Crystal form I has unit-cell parameters a = 44.75, b = 74.25, c = 48.32 Å and β = 114.14°. Unit-cell parameters for crystal form II are a = 47.86, b = 73.59, c = 80.49 Å and β = 98.54°. Crystal form I has a Vm of 2.295 Å3 Da−1 and an estimated solvent content of 46.4% with one molecule per asymmetric unit, while crystal form II has a Vm of 2.196 Å3 Da−1 and an estimated solvent content of 44.0%, assuming two molecules per asymmetric unit.

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.

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 Optimization of S-Nitrosocaptopril Monohydrate Storage Conditions Based on Response Surface Method

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7533
Author(s):  
Lingyi Huang ◽  
Yu Zhou ◽  
Yizhi Wang ◽  
Min Lin
Keyword(s):  
Response Surface ◽  
Enzyme Inhibitor ◽  
Storage Condition ◽  
Crystal Form ◽  
Storage Conditions ◽  
Specific Storage ◽  
No Donor ◽  
Steepest Ascent ◽  
Long Term Storage ◽  
Rough Interval

From unstable crystals to relatively stable monohydrate crystals, many researchers have been working on S-nitrosocaptopril for more than two decades. S-nitrosocaptopril monohydrate (Cap-NO·H2O) is a novel crystal form of S-nitrosocaptopril (Cap-NO), and is not only a nitric oxide (NO) donor, but also an angiotensin-converting enzyme inhibitor (ACEI). Yet, a method for long-term storage has never been reported. In order to determine the optimal storage conditions, Plackett–Burman (PB) design was performed to confirm the critical factors. Response surface methodology (RSM) was employed to determine the optimal Cap-NO·H2O storage condition, based on the rough interval determined by the path of steepest ascent experiment. The optimized storage condition was denoted as nitrogen purity of 97%, temperature of −10 °C and 1.20 g deoxidizer. In this case, a final preservation rate of 97.91 ± 0.59% could be obtained. In specific storage conditions, Cap-NO·H2O was found to be stable for at least 6 months in individual PE package, procreating a potentially applicable avenue.

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 One-Dimensional Heterogeneous Reaction Model of a Drop-Tube Carbonator Reactor for Thermochemical Energy Storage Applications

Energies ◽  
2020 ◽  
Vol 13 (22) ◽  
pp. 5905
Author(s):  
Evgenios Karasavvas ◽  
Athanasios Scaltsoyiannes ◽  
Andy Antzaras ◽  
Kyriakos Fotiadis ◽  
Kyriakos Panopoulos ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Energy Storage ◽  
Reaction Kinetics ◽  
Heterogeneous Reaction ◽  
Scale Up ◽  
Storage Conditions ◽  
Reaction Model ◽  
Drop Tube ◽  
Carbonation Reaction ◽  
One Dimensional

Calcium looping systems constitute a promising candidate for thermochemical energy storage (TCES) applications, as evidenced by the constantly escalating scientific and industrial interest. However, the technologically feasible transition from the research scale towards industrial and highly competitive markets sets as a prerequisite the optimal design and operation of the process, especially corresponding reactors. The present study investigates for the first time the development of a detailed, one-dimensional mathematical model for the steady-state simulation of a novel drop-tube carbonator reactor as a core equipment unit in a concentrated solar power (CSP)-thermochemical energy storage integration plant. A validated kinetic mathematical model for a carbonation reaction (CaO(s) + CO2(g) → CaCO3(s)) focused on thermochemical energy storage conditions was developed and implemented for different material conditions. The fast gas–solid reaction kinetics conformed with the drop-tube reactor concept, as the latter is suitable for very fast reactions. Reaction kinetics were controlled by the reaction temperature. Varying state profiles were computed across the length of the reactor by using a mathematical model in which reactant conversions, the reaction rate, and the temperature and velocity of gas and solid phases provided crucial information on the carbonator’s performance, among other factors. Through process simulations, the model-based investigation approach revealed respective restrictions on a tailor-made reactor of 10 kWth, pointing out the necessity of detailed models as a provision for design and scale-up studies.

scholarly journals Facile Synthesis of Novel Prussian Blue–Lipid Nanocomplexes

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4137 ◽  
Author(s):  
Maria Antònia Busquets ◽  
Ariadna Novella-Xicoy ◽  
Valeria Guzmán ◽  
Joan Estelrich
Keyword(s):  
Prussian Blue ◽  
Photothermal Therapy ◽  
Near Infrared ◽  
Fine Arts ◽  
Storage Conditions ◽  
High Yield ◽  
Facile Synthesis ◽  
Synthesis Procedure ◽  
Homogeneous Preparation

Prussian blue (PB) is known for its multiple applications ranging from fine arts to therapeutics. More recently, PB nanoparticles have been pointed to as appealing photothermal agents (PA) when irradiated with wavelengths corresponding to the biological windows, namely regions located in the near infrared (NIR) zone. In addition, the combination of PB with other components such as phospholipids boosts their therapeutical potential by facilitating, for instance, the incorporation of drugs becoming suitable drug delivery systems. The novelty of the research relies on the synthesis procedure and characterization of hybrid lipid–PB nanoparticles with a high yield in a friendly environment suitable for photothermal therapy. This goal was achieved by first obtaining insoluble PB coated with oleylamine (OA) to facilitate its combination with lipids. The resulting lipid–PB complex showed a monomodal distribution of sizes with an overall size of around 100 nm and a polydispersity index of about 0.200. It highlights one critical step in the synthesis procedure that is the shaking time of the mixture of PB–OA nanoparticles with the lipid, which was found to be 48 h. This time assured homogeneous preparation without the need of further separation stages. Samples were stable for more than three months under several storage conditions.

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