CSIRO RAMP / Stanford University
The outcomes of a 2018 collaboration between the RAMP Centre and researchers from the Appel Group at Stanford University were recently published in Science Translational Medicine.
Right now if you’re a Type I diabetic, you need to inject insulin at the appropriate time to process the glucose load from your food. Current products are slow to act, and have a residual release time in the body. That makes them inefficient, and inconvenient. The technology presented in this paper suggests a path towards new insulin formulations that are 1) fast acting, 2) have less residual time in the body, and 3) have a good “shelf life”. That means you could more reasonably inject your insulin at meal time (instead of 30-45 minutes ahead) for optimal effect. The result is better control of your blood sugar, and more convenience. CSIRO’s RAMP centre is proud to have made a contribution to this fantastic work by the Appel Group, and especially enjoyed hosting Anton A.A. Smith and Joseph L. Mann here in our Melbourne labs.
Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not act quickly enough to provide good control at mealtime. In the RAMP centre, we implement high-throughput, controlled, radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients (a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization) designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 hours, compared to 5 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine animal model of insulin-deficient diabetes, UFAL exhibited peak action at 9 min, whereas commercial Humalog exhibited peak action at 25 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.
See video footage from the RAMP centre at about 1:50, where you’ll see CSIRO and Stanford researchers working with the Chemspeed SWING XL platform housed in our labs.
European Polymer Journal
We describe the sequential incorporation of the quaternized monomer N-(2-(Methacryloyloxy)ethyl)-N,N-dimethylheptan-1-ammonium (QDM) (from 1 up to 5 mol %) into 2-((dimethylamino)ethyl methacrylate) polymer chains (PDMAEMA), via reversible addition-fragmentation chain transfer (RAFT) technique, to yield quasi-block copolymers (PDMAEMA-qb-P(DMAEMA-co-QDM)) with modified hydrophilic nature and thermo-induced self-assembly properties in aqueous solutions. This chemical modification promotes the formation of metastable nanostructures in aqueous medium. The morphological transitions were investigated by means of atomic force microscopy (AFM), dynamic light scattering (DLS), rheology and turbidimetry. The results indicated that the obtained nanostructures were stabilized by associative and cationic interactions conveyed by the quaternized moieties within the polymer chains. The size of these nanostructures could be modified as a function of molar mass, copolymer composition and temperature. The method described denotes an interesting alternative to modify the thermo-induced self-assembly behavior of PDMAEMA based copolymers employing low amounts of quaternized moieties.
March 09-11, 2020, Wotton-under-Edge UK – The meeting was organized by the Dial-a-Molecule, Directed Assembly, and AI3 Science Discovery Networks. Dial-a-Molecule’s vision is that in 20-40 years, scientists will be able to deliver any desired molecule within a timeframe useful to the end-user, using safe, economically viable and sustainable processes. Predicting the outcome of unknown reactions is a key challenge, and a key problem is lack of data, particularly on “failed” reactions. Synthesis must become a data-driven discipline.
Contribution using Chemspeed’s ISYNTH digitalizing, standardizing, accelerating automated synthesis solution: Encoding solvents and product outcomes to improve reaction prediction systems Dr. Ella M. Gale, University of Bristol
Catalysis Science & Technology
The reactivity of a phenoxy-imine-ether system (FI)TiCl3/MAO was studied toward selective ethylene trimerization. This system was shown to either trimerize or polymerize ethylene depending on the reaction temperature. Its selectivity switches from a significant production of the trimerization product, 1-hexene (85 wt%, 520–450 kg1-hexene gTi−1 h−1) between 30 and 40 °C, to a moderate polyethylene formation (70–80 wt%, 60–70 kgpolyethylene gTi−1 h−1) at a higher reaction temperature (T > 60 °C). Polymerization was investigated based on an original “polymer-to-catalyst” strategy aiming at identifying the active species responsible for this side reaction. Using DSC, SEC and high temperature 13C NMR analyses, polyethylenes were found to exhibit high molar masses (>105 g mol−1) and a low 1-hexene content (<1 mol%) at any temperature. Kinetic studies support that trimerization and polymerization species are generated from the catalyst precursor at 40 °C but a parallel process may occur at a higher temperature. The increase of dispersity to 4.6 at 80 °C suggests a change from single to multi-site catalysis. The poor comonomer incorporation ability of the active species is reminiscent of a molecular Ziegler–Natta or a bulky post-metallocene catalyst.
Chemical Communications Journal
The reaction of cyclic amides with acetylene under low pressure, using ruthenium-phosphine catalysts, afforded a broad variety of N-vinylated amides including (azabicyclic) lactams, oxazolidinones, benzoisoxazolones, isoindolinones, quinoxalinones, oxazinanones, cyclic urea derivatives (imidazolidinones), nucleobases (thymine), amino acid anhydrides and thiazolidinone.
Molecular Catalysis Journal
Diffusion and acidity of molecules are key parameters in organic synthesis; therefore, highly stable mesoporous HZSM-5 zeolites with ratios of Brønsted (CB) to Lewis (CL) acid sites tuned by alkaline desilication were employed for Friedel–Crafts acylation of anisole with acetic anhydride. Controlled zeolite desilication (Si/Al = 12 and 23) proceeded by varying the NaOH concentration, temperature, and treatment time. SEM/EDS, XRD, N2 physisorption, NH3-TPD, DRIFTS, and 29Si-MAS-NMR data were used to correlate the generated intracrystalline mesoporosity with the new textural, acidic, and catalytic properties. It was evidenced that desilication allowed the CB/CL ratio to vary from 21 to 2.3. During anisole acylation, the specific activity to 4-methoxyacetophenone (4-MAP), on a desilicated zeolite that preserved most of the original microstructure, markedly increased with increasing mesoporosity, even a decrease of the CB/CL ratio had occurred. The strong changes in the acid nature and textural properties did not change the anisole acylation acid mechanism and improved the internal diffusion of reactants and 4-MAP to or from the active sites, respectively. Thus, appropriate levels of mesoporosity with consequent acidity changes may be designed through controlled zeolite desilication, with the resultant hierarchical zeolite capable of being applied as a catalyst to a particular organic reaction mechanism.
Although the concept of quantum confinement was introduced more than thirty years ago, a wide application of the quantum dots is still limited by the fact that monodisperse quantum dots with controlled optoelectronic properties are typically synthesized on a relatively small scale. Larger scale synthesis techniques are usually not able to produce monodisperse nanoparticles yet. In this contribution, we illustrate the capability of the combination of transmission electron microscopy and X-ray diffraction to reveal detailed and scale-bridging information about the complex microstructure of non-monodisperse quantum dots, which is the first step towards a further upscalling of the techniques for production of quantum dots with controlled properties. As a model system, CdSe quantum dots synthesized using an automated robotic hot-injection method at different temperatures were chosen. The combined microstructure analytics revealed the size and shape of the CdSe nanocrystals and the kind, density and arrangement of planar defects. The role of the planar defects in the particle coarsening by oriented attachment and the effect of the planar fault arrangement on the phase constitution, on the crystallographic coherence of the counterparts and on the optoelectronic properties are discussed.
Combinatorial Science Journal
Translation of a manual process to high throughput for research and development requires special consideration. One important and often unreported aspect is the establishment of an eﬃcient cleaning routine. This becomes signiﬁcant, as precious time and, in particular, material would be lost, that is, when low-quality high-throughput experimentation is involved. We present a fully automated cleaning routine of the challenging synthesis of cadmium selenide quantum dots. Manual, semiautomated, and fully automated cleaning protocols were executed and compared in terms of spectral similarities of the synthesized colloids. Only the fully automated protocol enabled true 24/7 operation.
The selective hydroconversion of 5‐hydroxymethylfurfural (HMF) to biofuels is currently highly sought‐for. While the literature has demonstrated that this reaction is possible on promoted Ni catalysts, we show here that a monometallic, non‐promoted Ni/SBA‐15 catalyst, prepared by incipient wetness impregnation, can convert HMF to 2,5‐dimethylfuran (DMF) and to 2,5‐dimethyltetrahydrofuran (DMTHF) at 180 °C, in a consecutive way. Through a control over reaction time, high yields to DMF (71 %, at conversion of 93 %) or DMTHF (97 %, at conversion of 100 %) can be achieved. Kinetic modelling suggests a preferential route to DMF via 5‐methylfurfural (MFFR) as intermediate, though the route via 2,5‐bis(hydroxylmethyl)furan (BHMF) is also present. The favored route in the experimental conditions involves the hydrogenolysis of the hydroxyl group of HMF as first step, followed by the hydrogenation of the aldehyde function, to methylfurfuryl alcohol (MFOL). It is suggested a higher reaction rate of hydrogenation or hydrogenolysis of the side group is linked to the presence of a methyl group in the molecule. No hydrogenation of the furan ring is detected on the intermediates.
An enzyme degassing method for oxygen-intolerant polymerizations was implemented in a commercially available automated parallel synthesizer and tested for reversible addition–fragmentation chain transfer (RAFT) polymerizations performed in open vessels. For this purpose, a recently reported methodology that employs the enzyme glucose oxidase (GOx) to deplete oxygen in reaction media was utilized. The effectiveness of this approach to perform unattended parallel polymerization reactions in open vessels was demonstrated by comparing experimental results to those obtained under similar experimental conditions but utilizing the common degassing method of sparging N2 to remove oxygen. The proposed experimental technique displayed good precision in performing RAFT polymerizations and good control of the obtained polymers and could be easily adapted to other systems where the removal of oxygen is mandatory. This alternative high-throughput/high-output method may have the potential to increase productivity in research projects where oxygen-intolerant reactions are involved.