Radio Frequency - Assisted Ultrasonic Spray Freeze Drying for Pharmaceutical Protein Solids.

This study examined physical stability of spray freeze dried (SFD) bovine serum albumin (BSA) solids produced using the radio frequency (RF)-assisted drying technique. BSA formulations were prepared with varying concentrations of trehalose and mannitol, using an excipient-free formulation as control. These formulations were produced using either traditional ultrasonic spray freeze drying (SFD) or RF-assisted ultrasonic spray freeze drying (RFSFD). The dried formulations were then characterized using Karl Fischer moisture content measurement, powder X-ray diffraction (PXRD), size exclusion chromatography (SEC), and solid-state hydrogen/deuterium exchange with mass spectrometry (ssHDX-MS). Moisture content did not have a good correlation with the physical stability of the formulations measured by SEC. ssHDX-MS metrics such as deconvoluted peak areas of the deuterated samples showed a satisfactory correlation (R2 = 0.914) with the SEC stability data. RFSFD improved the stability of formulations with 20 mg/ml of trehalose and no mannitol, and had similar stability with all other formulations as compared to SFD. This study demonstrated that RFSFD technique can significantly reduce the duration of primary drying cycle from 48.0 h to 27.5 h while maintaining or improving protein physical stability as compared to traditional lyophilization.

Noble-Nanoparticle-Decorated Ti3C2T x MXenes for Highly Sensitive Volatile Organic Compound Detection.

Two-dimensional transition-metal carbides and nitrides (MXenes) have been regarded as promising sensing materials because of their high surface-to-volume ratios and outstanding electronic, optical, and mechanical properties with versatile transition-metal and surface chemistries. However, weak gas-molecule adsorption of MXenes poses a serious limitation to their sensitivity and selectivity, particularly for trace amounts of volatile organic compounds (VOCs) at room temperature. To deal with these issues, Au-decorated MXenes are synthesized by a facile solution mixing method for room-temperature sensing of a wide variety of oxygen-based and hydrocarbon-based VOCs. Dynamic sensing experiments reveal that optimal decoration of Au nanoparticles (NPs) on Ti3C2T x MXene significantly elevates the response and selectivity of the flexible sensors, especially in detecting formaldehyde. Au-Ti3C2T x gas sensors exhibited an extremely low limit of detection of 92 ppb for formaldehyde at room temperature. Au-Ti3C2T x provides reliable gas response, low noise level, ultrahigh signal-to-noise ratio, high selectivity, as well as parts per billion level of formaldehyde detection. The prominent mechanism for Au-Ti3C2T x in sensing formaldehyde is elucidated theoretically from density functional theory simulations. The results presented here strongly suggest that decorating noble-metal NPs on MXenes is a feasible strategy for the development of next-generation ultrasensitive sensors for Internet of Things.

A non-invasive multipoint product temperature measurement for pharmaceutical lyophilization.

Monitoring product temperature during lyophilization is critical, especially during the process development stage, as the final product may be jeopardized if its process temperature exceeds a threshold value. Also, in-situ temperature monitoring of the product gives the capability of creating an optimized closed-loop lyophilization process. While conventional thermocouples can track product temperature, they are invasive, limited to a single-point measurement, and can significantly alter the freezing and drying behavior of the product in the monitored vial. This work has developed a new methodology that combines non-invasive temperature monitoring and comprehensive modeling. It allows the accurate reconstruction of the complete temperature profile of the product inside the vial during the lyophilization process. The proposed methodology is experimentally validated by combining the sensors' wirelessly collected data with the advanced multiphysics simulations. The flexible wireless multi-point temperature sensing probe is produced using micro-manufacturing techniques and attached outside the vial, allowing for accurate extraction of the product temperature.

Statistical electromagnetics for industrial pharmaceutical lyophilization.

Lyophilization is a common unit operation in pharmaceutical manufacturing but is a prolonged vacuum drying process with poor energy utilization. Microwave-assisted vacuum drying has been investigated to accelerate the lyophilization process. However, the literature lacks methodical approaches that consider the lyophilizer, the lyophilizate, the microwave power uniformity, the resulting heat uniformity, and the scalability. We present a microwave-vacuum drying method based on the statistical electromagnetics theory. The method offers an optimum frequency selection procedure that accounts for the lyophilizer and the lyophilizate. The 2.45 GHz frequency conventionally utilized is proven to be far from optimum. The method is applied in a microwave-assisted heating configuration to pharmaceutical excipients (sucrose and mannitol) and different myoglobin formulations in a lab-scale lyophilizer. At 18 GHz frequency and 60 W microwave power, the method shows nearly three times speed-up in the primary drying stage of sucrose relative to the conventional lyophilization cycle for typical laboratory batches. The uniformity of the microwave power inside the chamber is controlled within ± 1 dB. The resulting heating uniformity measured through residual moisture analysis shows 12.7% of normalized SD of moisture level across the batch in a microwave-assisted cycle as opposed to 15.3% in the conventional cycle. Conventional and microwave lyophilized formulations are characterized using solid-state hydrogen-deuterium exchange-mass spectrometry (ssHDX-MS), solid-state Fourier transform infrared spectroscopy (ssFTIR), circular dichroism (CD), and accelerated stability testing (AST). Characterization shows comparable protein structure and stability. Heat and mass transfer simulations quantify further effects of optimal volumetric heating via the high-frequency statistical microwave heating.

Antidelaminating, Thermally Stable, and Cost-Effective Flexible Kapton Platforms for Nitrate Sensors, Mercury Aptasensors, Protein Sensors, and p-Type Organic Thin-Film Transistors.

The inkjet printing of metal electrodes on polymer films is a desirable manufacturing process due to its simplicity but is limited by the lack of thermal stability and serious delaminating flaws in various aqueous and organic solutions. Kapton, adopted worldwide due to its superior thermal durability, allows the high-temperature sintering of nanoparticle-based metal inks. By carefully selecting inks (Ag and Au) and Kapton substrates (Kapton HN films with a thickness of 135 µm and a thermal resistance of up to 400 °C) with optimal printing parameters and simplified post-treatments (sintering), outstanding film integrity, thermal stability, and antidelaminating features were obtained in both aqueous and organic solutions without any pretreatment strategy (surface modification). These films were applied in four novel devices: a solid-state ion-selective (IS) nitrate (NO3-) sensor, a single-stranded DNA (ssDNA)-based mercury (Hg2+) aptasensor, a low-cost protein printed circuit board (PCB) sensor, and a long-lasting organic thin-film transistor (OTFT). The IS NO3- sensor displayed a linear sensitivity range between 10-4.5 and 10-1 M (r2 = 0.9912), with a limit of detection of 2 ppm for NO3-. The Hg2+ sensor exhibited a linear correlation (r2 = 0.8806) between the change in the transfer resistance (RCT) and the increasing concentration of Hg2+. The protein PCB sensor provided a label-free method for protein detection. Finally, the OTFT demonstrated stable performance, with mobility values in the linear (µlin) and saturation (µsat) regimes of 0.0083 ± 0.0026 and 0.0237 ± 0.0079 cm2 V-1 S-1, respectively, and a threshold voltage (Vth) of -6.75 ± 3.89 V.

Surface Functionalization of Ti3C2Tx MXene with Highly Reliable Superhydrophobic Protection for Volatile Organic Compounds Sensing.

Two-dimensional (2D) transition-metal carbides (Ti3C2Tx MXene) have received a great deal of attention for potential use in gas sensing showing the highest sensitivity among 2D materials and good gas selectivity. However, one of the long-standing challenges of the MXenes is their poor stability against hydration and oxidation in a humid environment, limiting their long-term storage and applications. Integration of an effective protection layer with MXenes shows promise for overcoming this major drawback. Herein, we demonstrate a surface functionalization strategy for Ti3C2Tx with fluoroalkylsilane (FOTS) molecules through surface treatment, providing not only a superhydrophobic surface, mechanical/environmental stability but also enhanced sensing performance. The experimental results show that high sensitivity, good repeatability, long-term stability, and selectivity and faster response/recovery property were achieved by the FOTS-functionalized when Ti3C2Tx was integrated into chemoresistive sensors sensitive to oxygen-containing volatile organic compounds (ethanol, acetone). FOTS functionalization provided protection to sensing response when the dynamic response of the Ti3C2Tx-F sensor to 30 ppm of ethanol was measured over in the 5 to 80% relative humidity range. Density functional theory simulations suggested that the strong adsorption energy of ethanol on Ti3C2Tx-F and the local structure deformation induced by ethanol adsorption, contributing to the gas-sensing enhancement. This study offers a facile and practical solution for developing highly reliable MXene based gas-sensing devices with response that is stable in air and in the presence of water.

Selective Detection of Ethylene by MoS2-Carbon Nanotube Networks Coated with Cu(I)-Pincer Complexes.

The plant hormone ethylene (C2) can induce premature fruit ripening and flower senescence at levels below 1 ppm, which has motivated efforts to develop cost-effective methods for C2 monitoring during the transport and storage of climacteric fruits. Here, we describe a nanocomposite film composed of exfoliated MoS2, single-walled carbon nanotubes (SCNTs), and Cu(I)-tris(mercaptoimidazolyl)borate complexes (Cu-Tm) for real-time detection of C2 at levels down to 100 ppb. A copercolation network of MoS2 and SCNTs was deposited onto interdigitated Ag electrodes printed on plastic substrates and then coated with Cu-Tm with a final conductance in the 0.5 mS range. Reversible changes in relative conductance (-ΔG/G0) were measured upon C2 exposure with a linear response at sub-ppm levels. The thin-film sensors were highly selective toward C2, and they responded weakly to other volatile organic compounds or water at similar partial pressures. A mechanism is proposed in which Cu-Tm behaves as a chemically sensitive n-type dopant for MoS2, based on spectroscopic characterization and density functional theory modeling. Cu-Tm-coated MoS2/SCNT sensors were also connected to a battery-powered wireless transmitter and used to monitor C2 production from various fruit samples, validating their utility as practical, field-deployable sensors.

Nanohybrids of a MXene and transition metal dichalcogenide for selective detection of volatile organic compounds.

Two-dimensional transition metal carbides/nitrides, known as MXenes, have been recently receiving attention for gas sensing. However, studies on hybridization of MXenes and 2D transition metal dichalcogenides as gas-sensing materials are relatively rare at this time. Herein, Ti3C2Tx and WSe2 are selected as model materials for hybridization and implemented toward detection of various volatile organic compounds. The Ti3C2Tx/WSe2 hybrid sensor exhibits low noise level, ultrafast response/recovery times, and good flexibility for various volatile organic compounds. The sensitivity of the hybrid sensor to ethanol is improved by over 12-fold in comparison with pristine Ti3C2Tx. Moreover, the hybridization process provides an effective strategy against MXene oxidation by restricting the interaction of water molecules from the edges of Ti3C2Tx. An enhancement mechanism for Ti3C2Tx/WSe2 heterostructured materials is proposed for highly sensitive and selective detection of oxygen-containing volatile organic compounds. The scientific findings of this work could guide future exploration of next-generation field-deployable sensors.

Multi-Point Wireless Temperature Sensing System for Monitoring Pharmaceutical Lyophilization.

This work presents the design and evaluation of a fully wireless, multi-point temperature sensor system as a Process Analytical Technology (PAT) for lyophilization. Each sensor contains seven sensing elements which measure the product temperature at various positions of the contents of a glass vial. The sensor performance was studied by freeze drying experiments with sensor placement in both center and edge of full shelf of 6R glass vials with 4 ml fill volume. Product temperature profile and primary drying time measured at the bottom center position in the glass vial by the wireless sensor as well as the primary drying time are in close comparison with the thermocouple data. The drying times during primary drying were determined at the top, higher middle, lower middle and bottom positions which are 3.26 mm apart vertically in the vial by the wireless sensor based on the temperature profile measured at different positions. For a center vial, the drying time from the start of primary drying to each layer was measured at 3.9, 9.3, 14.2, and 21 h respectively, allowing to track the sublimation interface during primary drying phase. In addition, sublimation rate at each layer was calculated based on the drying time and theoretical weight loss of ice in the product. The sublimation rate at the beginning of the primary drying was similar to the sublimation rate by gravimetric method. Furthermore, the vial heat transfer coefficient (Kv ) was also calculated based on the sublimation rate. Thus, allowing the use of the multi-point wireless sensor to rapidly monitor the sublimation rate and Kv for every batch as continuous process verification. Similar tests were also conducted with 3% w/v mannitol solutions and the results were consistent demonstrating potential for real-time monitoring, process verification and cycle optimization for pharmaceutical lyophilization.

Real-time DC-dynamic biasing method for switching time improvement in severely underdamped fringing-field electrostatic MEMS actuators.

Mechanically underdamped electrostatic fringing-field MEMS actuators are well known for their fast switching operation in response to a unit step input bias voltage. However, the tradeoff for the improved switching performance is a relatively long settling time to reach each gap height in response to various applied voltages. Transient applied bias waveforms are employed to facilitate reduced switching times for electrostatic fringing-field MEMS actuators with high mechanical quality factors. Removing the underlying substrate of the fringing-field actuator creates the low mechanical damping environment necessary to effectively test the concept. The removal of the underlying substrate also a has substantial improvement on the reliability performance of the device in regards to failure due to stiction. Although DC-dynamic biasing is useful in improving settling time, the required slew rates for typical MEMS devices may place aggressive requirements on the charge pumps for fully-integrated on-chip designs. Additionally, there may be challenges integrating the substrate removal step into the back-end-of-line commercial CMOS processing steps. Experimental validation of fabricated actuators demonstrates an improvement of 50x in switching time when compared to conventional step biasing results. Compared to theoretical calculations, the experimental results are in good agreement.

Low-frequency meandering piezoelectric vibration energy harvester.

The design, fabrication, and characterization of a novel low-frequency meandering piezoelectric vibration energy harvester is presented. The energy harvester is designed for sensor node applications where the node targets a width-to-length aspect ratio close to 1:1 while simultaneously achieving a low resonant frequency. The measured power output and normalized power density are 118 µW and 5.02 µW/mm(3)/g(2), respectively, when excited by an acceleration magnitude of 0.2 g at 49.7 Hz. The energy harvester consists of a laser-machined meandering PZT bimorph. Two methods, strain-matched electrode (SME) and strain-matched polarization (SMP), are utilized to mitigate the voltage cancellation caused by having both positive and negative strains in the piezoelectric layer during operation at the meander's first resonant frequency. We have performed finite element analysis and experimentally demonstrated a prototype harvester with a footprint of 27 x 23 mm and a height of 6.5 mm including the tip mass. The device achieves a low resonant frequency while maintaining a form factor suitable for sensor node applications. The meandering design enables energy harvesters to harvest energy from vibration sources with frequencies less than 100 Hz within a compact footprint.

DNA counterion current and saturation examined by a MEMS-based solid state nanopore sensor.

Reports of DNA translocation measurements have been increasing rapidly in recent years due to advancements in pore fabrication and these measurements continue to provide insight into the physics of DNA translocations through MEMS based solid state nanopores. Specifically, it has recently been demonstrated that in addition to typically observed current blockages, enhancements in current can also be measured under certain conditions. Here, we further demonstrate the power of these nanopores for examining single DNA molecules by measuring these ionic currents as a function of the applied electric field and show that the direction of the resulting current pulse can provide fundamental insight into the physics of condensed counterions and the dipole saturation in single DNA molecules. Expanding on earlier work by Manning and others, we propose a model of DNA counterion ionic current and saturation of this current based on our experimental results. The work can have broad impact in understanding DNA sensing, DNA delivery into cells, DNA conductivity, and molecular electronics.