Towards a digital twin for analytical HPLC

Digital twins for industrial process development are quickly gaining popularity in the pharmaceutical industry as an effective alternative to expensive and time-consuming physical experiments. This work describes the digital model element of a digital twin of High-Performance Liquid Chromatography (HPLC). The model is based on a mechanistic model implemented in gPROMS ModelBuilder and integrated into the MATLAB environment. Unlike other models reported in the literature, our model comprises a more accurate prediction of the injection profile and can predict the elution behaviour for a wide range of HPLC conditions given a reduced number of experiments. The model is compared against experimental data performed to separate a mixture of eight small drug molecules on a C18 column, in gradient elution mode, and under nine different operative conditions (i.e. 3 temperatures × 3 solvent gradient). We will show that by considering only two isotherm parameters for each molecule, the digital model can accurately predict the retention behaviour of the eight analytes. Furthermore, it facilitates HPLC in-silico method development, showcased here via method time minimization through a dynamic solvent strength gradient. The proposed model is intended to be integrated into a digital twin architecture for offline decision support and real-time optimization

Co-precipitation synthesis of stable iron oxide nanoparticles with NaOH: New insights and continuous production via flow chemistry

Co-precipitation is by far the most common synthesis for magnetic iron oxide nanoparticles (IONPs), as cheap and environmentally friendly precursors and simple experimental procedures facilitate IONP production in many labs. Optimising co-precipitation syntheses remains challenging however, as particle formation mechanisms are not well understood. This is partly due to the rapid particle formation (within seconds) providing insufficient time to characterise initial precipitates. To overcome this limitation, a flow chemistry approach has been developed using steady-state operation to “freeze” transient reaction states locally. This allowed for the first time a comprehensive analysis of the early stages of co-precipitation syntheses via in-situ Small Angle X-ray Scattering and in-situ synchrotron X-Ray Diffraction. These studies revealed that after mixing the ferrous/ferric chloride precursor with the NaOH base solution, the most magnetic iron oxide phase forms within 5 s, the particle size changes only marginally afterwards, and co-precipitation and agglomeration occur simultaneously. As these agglomerates were too large to achieve colloidal stability via subsequent stabiliser addition, co-precipitated IONPs had to be de-agglomerated. This was achieved by adding the appropriate quantity of a citric acid solution which yielded within minutes colloidally stable IONP solutions around a neutral pH value. The new insights into the particle formation and the novel stabilisation procedure (not requiring any ultra-sonication or washing step) allowed to design a multistage flow reactor to synthesise and stabilise IONPs continuously with a residence time of less than 5 min. This reactor was robust against fouling and produced stable IONP solutions (of ~1.5 mg particles per ml) reproducibly via fast mixing ( 500 ml/h) for low materials cost

Development and implementation of a pneumatic micro-feeder for poorly-flowing solid pharmaceutical materials

Consistent powder micro-feeding (and reduces manufacturing waste. Current commercial micro-feeders are limited in their ability to feed < 20 g/h of cohesive (i.e. powders of poor flowability) active pharmaceutical ingredients (API) and excipients (e.g. lubricants) with low fluctuation. To breach this gap, this study presents an advanced micro-feeder design capable of feeding a range of pharmaceutical-grade powders consistently at flow rates as low as 0.7 g/h with to minimise flow rate variations. This work details the design of this pneumatic micro-feeder and its excellent micro-feeding performance even for cohesive powders. The experimental studies investigated the influence of the process parameters (air pressure and air flow rate) and equipment configurations (insert size and plug position) on the feeding performance of different pharmaceutical-relevant powders, i.e., microcrystalline cellulose (MCC), croscarmellose sodium (CCS), crospovidone (XPVP) and paracetamol (APAP). It was shown that the system is capable of delivering consistent powder flow rates with good repeatability and stability

Droplet-based millifluidic synthesis of a proton-conducting sulfonate metal–organic framework

Metal–organic frameworks (MOFs) have emerged as promising candidate materials for proton exchange membranes (PEMs), due to the control of proton transport enabled by functional groups and the structural order within the MOFs. In this work, we report a millifluidic approach for the synthesis of a MOF incorporating both sulfonate and amine groups, termed Cu-SAT, which exhibits a high proton conductivity. The fouling-free multiphase flow reactor synthesis was operated for more than 5 h with no reduction in yield or change in the particle size distribution, demonstrating a sustained space–time yield up to 131.7 kg m−3 day−1 with consistent particle quality. Reaction yield and particle size were controllably tuned by the adjustment of reaction parameters, such as residence/reaction time, temperature, and reagent concentration. The reaction yields from the flow reactor were 10–20% higher than those of corresponding batch syntheses, indicating improved mass and heat transfer in flow. A systematic exploration of synthetic parameters using a factorial design of experiments approach revealed the key correlations between the process parameters and yields and particle size distributions. The proton conductivity of the synthesized Cu-SAT MOF was evaluated in a mixed matrix membrane model PEM with polyvinylpyrrolidone and polyvinylidene fluoride polymers, exhibiting a promising composite conductivity of 1.34 ± 0.05 mS cm−1 at 353 K and 95% relative humidity (RH)

New Insight Into the Effect of Mass Transfer on the Synthesis of Silver and Gold Nanoparticles.

The fact that mass transfer affects noble metal nanoparticle (NP) syntheses is well known, not least because the scale-up of batch processes is anything but trivial. Therefore, this work studies the synthesis of silver and gold nanoparticles in batch reactors using constant reactant concentrations, but different process conditions to alter the mass transfer during the synthesis. Silver NPs were synthesized by reduction of silver nitrate via sodium borohydride in the presence of trisodium citrate. Gold NPs were synthesized using the Turkevich method, reducing tetrachloroauric acid via trisodium citrate. Four synthesis conditions for each NP system were used to investigate the mass transfer effects on the size and dispersity of the NPs. These were the i) slow or ii) fast addition of the concentrated reducing agent to the dilute precursor and the iii) slow and iv) fast addition of the concentrated precursor to dilute reducing agent solutions. Slow addition was performed by adding the reagent dropwise at a rate of 0.5 ml min−1 from a tube suspended above the stirred bulk solution, while fast addition was achieved by adding the reagent near the stir bar tip at a rate of 50 ml min−1 from a tube submerged in the stirred bulk solution. Mixing times of 209 ms for slow and 46 ms for fast reagent addition were determined using the Villermaux–Dushman protocol in combination with a mixing model. The silver NP size ranged from 6.7 to 11.5 nm for the four mixing conditions tested, with the smallest NPs being synthesized by fast addition of sodium borohydride to a silver nitrate solution. Stabilization of the initially formed particles was key to producing smaller and less polydisperse silver NPs in the case of slow reagent addition. The gold NP size ranged from 13.1 to 18.0 nm, with the smallest NPs being synthesized by fast addition of the trisodium citrate solution to the tetrachloroauric acid precursor solution. Faster reagent addition reduced polydispersity, due to a sharper separation of nucleation and growth. The results for both systems highlight the importance of mass transfer in determining the size and degree of polydispersity in batch synthesis of NPs and indicate that the effects are system-dependent

Droplet-based millifluidic synthesis of a proton-conducting sulfonate metal–organic framework

Metal–organic frameworks (MOFs) have emerged as promising candidate materials for proton exchange membranes (PEMs), due to the control of proton transport enabled by functional groups and the structural order within the MOFs. In this work, we report a millifluidic approach for the synthesis of a MOF incorporating both sulfonate and amine groups, termed Cu-SAT, which exhibits a high proton conductivity. The fouling-free multiphase flow reactor synthesis was operated for more than 5 h with no reduction in yield or change in the particle size distribution, demonstrating a sustained space–time yield up to 131.7 kg m−3 day−1 with consistent particle quality. Reaction yield and particle size were controllably tuned by the adjustment of reaction parameters, such as residence/reaction time, temperature, and reagent concentration. The reaction yields from the flow reactor were 10–20% higher than those of corresponding batch syntheses, indicating improved mass and heat transfer in flow. A systematic exploration of synthetic parameters using a factorial design of experiments approach revealed the key correlations between the process parameters and yields and particle size distributions. The proton conductivity of the synthesized Cu-SAT MOF was evaluated in a mixed matrix membrane model PEM with polyvinylpyrrolidone and polyvinylidene fluoride polymers, exhibiting a promising composite conductivity of 1.34 ± 0.05 mS cm−1 at 353 K and 95% relative humidity (RH)

Inexpensive method for producing macroporous silicon particulates (MPSPs) with pyrolyzed polyacrylonitrile for lithium ion batteries

One of the most exciting areas in lithium ion batteries is engineering structured silicon anodes. These new materials promise to lead the next generation of batteries with significantly higher reversible charge capacity than current technologies. One drawback of these materials is that their production involves costly processing steps, limiting their application in commercial lithium ion batteries. In this report we present an inexpensive method for synthesizing macroporous silicon particulates (MPSPs). After being mixed with polyacrylonitrile (PAN) and pyrolyzed, MPSPs can alloy with lithium, resulting in capacities of 1000 mAhg−1 for over 600+ cycles. These sponge-like MPSPs with pyrolyzed PAN (PPAN) can accommodate the large volume expansion associated with silicon lithiation. This performance combined with low cost processing yields a competitive anode material that will have an immediate and direct application in lithium ion batteries

Whither Magnetic Hyperthermia? A Tentative Roadmap

The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia