Modelling the controlled drug release of push-pull osmotic pump tablets using DEM.

The push-pull osmotic pump tablet is a promising drug delivery approach, offering advantages over traditional dosage forms in achieving consistent and predictable drug release rates. In the current study, the drug release process of push-pull osmotic pump tablets is modelled for the first time using the discrete element method (DEM) incorporated with a microscopic diffusion-induced swelling model. The effects of dosage and formulation design, such as delivery orifice size, drug-to-polymer ratio, tablet surface curvature, friction between particles and cohesion of polymer particles, on the drug release performance are systematically analysed. Numerical results reveal that an enlarged delivery orifice significantly increases both the total drug release and the drug release rate. Moreover, the larger the swellable particle component in the tablet, the higher the drug release rate. Furthermore, the tablet surface curvature is found to affect the drug release profile, i.e. the final drug release percentage increases with the increasing tablet surface curvature. It is also found that the drug release rate could be controlled by adjusting the inter-particle friction and the cohesion of polymer particles in the formulation. This DEM study offers valuable insights into the mechanisms governing drug release in push-pull osmotic pump tablets.

Bidirectional causality between idiopathic sudden sensorineural hearing loss and depression: a Mendelian randomization study.

Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) is a sudden onset, unexplained sensorineural hearing loss. Depression is a common mental disorder and a leading cause of disability. Here, We used a two-sample Mendelian randomization approach using pooled statistics from genome-wide association studies of ISSHL (1491 cases, 196,592 controls) and depression (23,424 cases, 192,220 controls) in European populations. This study investigated the bidirectional relationship between single nucleotide polymorphisms associated with depression and ISSHL using inverse variance weighting.Additional sensitivity analyses, such as Mendelian randomization-Egger (MR-Egger), weighted median estimates, and leave-one-out analysis, were performed to assess the reliability of the findings. Significant causal association between genetic susceptibility to ISSHL and depression in a random-effects IVW approach (OR = 1.037, 95% CI = 1.004-1.072, P = 0.030). In contrast, genetic depression was not risk factors for ISSHL (OR = 1.134, 95% CI = 0.871-1.475, P = 0.350). After validation by different MR methods and the sensitivity analysis, all of the above results are consistent. The evidence we have gathered suggests a causal relationship between ISSHL and depression. The presence of the former induces or further exacerbates the latter, whereas a similar situation does not exist when the latter is an influencing factor.

Dataset of the temperature rise during granular flows in a rotating drum.

This paper provides experimental data on the temperature rise during granular flows in a small-scale rotating drum due to heat generation. All heat is believed to be generated by conversion of some mechanical energy, through mechanisms such as friction and collisions between particles and between particles and walls. Particles of different material types were used, while multiple rotation speeds were considered, and the drum was filled with different amounts of particles. The temperature of the granular materials inside the rotating drum was monitored using a thermal camera. The temperature increases at specific times of each experiment are presented in form of tables, along with the average and standard deviation of the repetitions of each setup configuration. The data can be used as a reference to set the operating conditions of rotating drums, in addition to calibrating numerical models and validating computer simulations.

Numerical analysis of die filling with a forced feeder using GPU-enhanced discrete element methods.

Understanding die filling behaviour of powders is critical in developing optimal formulation and processes in various industries, such as pharmaceuticals and fine chemicals. In this paper, forced die filling is analysed using a graphics processing unit (GPU) based discrete element method (DEM), for which a powder feeder equipped with a wired stirrer is considered. The influences of operating parameters, such as the initial powder bed height, the filling speed, and the stirrer speed, on the die filling performance are systematically explored. It is shown that a larger initial powder bed height leads to a higher filling ratio, which can be attributed to a higher filling intensity; while the deposited particle mass in the die is almost independent of the powder bed height, when the initial fill level is larger than a critical bed height. Additionally, the filling ratio slightly increases with the increase of stirrer speed for cases with a stirrer, while the filling ratios are lower than that without a stirrer, which is attributed to the stirrer occupying some space above the die and reducing the effective discharge area. The obtained results can provide useful information for optimising the feeder system design and the operating condition.

Genomic Island-Mediated Horizontal Transfer of the Erythromycin Resistance Gene erm(X) among Bifidobacteria.

Antibiotic resistance is a serious medical issue driven by antibiotic misuse. Bifidobacteria may serve as a reservoir for antibiotic resistance genes (ARGs) that have the potential risk of transfer to pathogens. The erythromycin resistance gene erm(X) is an ARG with high abundance in bifidobacteria, especially in Bifidobacterium longum species. However, the characteristics of the spread and integration of the gene erm(X) into the bifidobacteria genome are poorly understood. In this study, 10 tetW-positive bifidobacterial strains and 1 erm(X)-positive bifidobacterial strain were used to investigate the transfer of ARGs. Conjugation assays found that the erm(X) gene could transfer to five other bifidobacterial strains. Dimethyl sulfoxide (DMSO) and vorinostat significantly promoted the transfer of the erm(X) from strain Bifidobacterium catenulatum subsp. kashiwanohense DSM 21854 to Bifidobacterium longum subsp. suis DSM 20211. Whole-genome sequencing and comparative genomic analysis revealed that the erm(X) gene was located on the genomic island BKGI1 and that BKGI1 was conjugally mobile and transferable. To our knowledge, this is the first report that a genomic island-mediated gene erm(X) transfer in bifidobacteria. Additionally, BKGI1 is very unstable in B. catenulatum subsp. kashiwanohense DSM 21854 and transconjugant D2TC and is highly excisable and has an intermediate circular formation. In silico analysis showed that the BKGI1 homologs were also present in other bifidobacterial strains and were especially abundant in B. longum strains. Thus, our results confirmed that genomic island BKGI1 was one of the vehicles for erm(X) spread. These findings suggest that genomic islands play an important role in the dissemination of the gene erm(X) among Bifidobacterium species. IMPORTANCE Bifidobacteria are a very important group of gut microbiota, and the presence of these bacteria has many beneficial effects for the host. Thus, bifidobacteria have attracted growing interest owing to their potential probiotic properties. Bifidobacteria have been widely exploited by the food industry as probiotic microorganisms, and some species have a long history of safe use in food and feed production. However, the presence of antibiotic resistance raises the risk of its application. In this study, we analyzed the transfer of the erythromycin resistance gene erm(X) and revealed that the molecular mechanism behind the spread of the gene erm(X) was mediated by genomic island BKGI1. To the best of our knowledge this is the first report to describe the transfer of the gene erm(X) via genomic islands among bifidobacteria. This may be an important way to disseminate the gene erm(X) among bifidobacteria.

Powder flow during linear and rotary die filling.

In the pharmaceutical industry, linear die filling is widely employed in R&D, while rotary die filling is very common in commercial production. It is not clear if powder die filling behaviour in a linear die filling system is representative of the flow performance in a rotary tablet press. In this study, a linear die filling system and a rotary die filling system were used to examine flow behaviours of both poor-flowing and free-flowing powders. It was found that the performance of poor-flowing powder in the linear die filling system is slightly better than that in the rotary die filling system, while the performance of free-flowing powders in the linear die filling system is similar to that in the rotary die filling system. Hence, it is suitable to use the linear die filling system to estimate the flow behaviour during rotary die filling with free-flowing powders, but caution needs to be taken when poor-flowing powders are used.

Impact breakage of single pharmaceutical tablets in an air gun.

Milling is commonly used for controlling the size distribution of granules in the pharmaceutical dry granulation process. A thorough understanding of the breakage of single compacts is crucial in unravelling the complex interactions that exist between different pharmaceutical feed materials and the mill process conditions. However, limited studies in the literature have examined the impact breakage of single pharmaceutical compacts. In this study, pharmaceutical powders including the microcrystalline MCC 101, MCC 102 and MCC DG were compressed at different pressures and tablets with different porosities and thicknesses were produced. Impact breakage tests were conducted in an air gun and the tablet impact velocities and breakage patterns were analysed using a Phantom ultrahigh-speed camera. It was observed that the tablet breakage rate and the amount of fines reduced as the tablet porosity decreased. In addition, thin tablets with low porosity exhibited semi-brittle fracture and less intense crack propagation while thick tablets with high porosity primarily disintegrated into fine fragments. Thus, this study provides a better understanding of the breakage behaviour of different pharmaceutical materials and can potentially be used to describe the breakage modes of compacts in the ribbon milling processes.

Modeling of a Soft-Rigid Gripper Actuated by a Linear-Extension Soft Pneumatic Actuator.

Soft robot has been one significant study in recent decades and soft gripper is one of the popular research directions of soft robot. In a static gripping system, excessive gripping force and large deformation are the main reasons for damage of the object during the gripping process. For achieving low-damage gripping to the object in static gripping system, we proposed a soft-rigid gripper actuated by a linear-extension soft pneumatic actuator in this study. The characteristic of the gripper under a no loading state was measured. When the pressure was >70 kPa, there was an approximately linear relation between the pressure and extension length of the soft actuator. To achieve gripping force and fingertip displacement control of the gripper without sensors integrated on the finger, we presented a non-contact sensing method for gripping state estimation. To analyze the gripping force and fingertip displacement, the relationship between the pressure and extension length of the soft actuator in loading state was compared with the relationship under a no-loading state. The experimental results showed that the relative error between the analytical gripping force and the measured gripping force of the gripper was ≤2.1%. The relative error between analytical fingertip displacement and theoretical fingertip displacement of the gripper was ≤7.4%. Furthermore, the low damage gripping to fragile and soft objects in static and dynamic gripping tests showed good performance of the gripper. Overall, the results indicated the potential application of the gripper in pick-and-place operations.

Impact of feed material properties on the milling of pharmaceutical ribbons: A PBM analysis.

Dry granulation is commonly used in the pharmaceutical industry for compressing heat and moisture sensitive feed materials into compacts, subsequently followed by milling. Population balance models (PBMs) are often used to explore the effects of milling conditions on the granule size distribution (GSD) but limited studies have investigated the effects of the feed material and ribbon properties on the resulting GSD. In this work, a variety of feed materials and ribbons with different mechanical properties were used to validate a mass-based bi-modal breakage function developed in a previous study (Olaleye et al., 2019). Ribbon like tablets (referred to as ribblets) with a range of precisely controlled porosities were produced using an Instron machine and pharmaceutical excipients including the microcrystalline cellulose MCC 101, MCC DG and a DCPA/MCC mixture. Roll compacted ribbons were also produced using MCC 102 and MCC DG excipients. The ribblets and ribbons were milled in an impact-dominated cutting mill and PBM parameters were obtained from the ribblet milling data. Mechanistic models related to the feed ribbon property were then developed. It was found that the PBM with the mass-based bi-modal breakage function can accurately predict the GSDs of both the milled ribblets and roll compacted ribbons. The model developed was successfully linked to ribbon properties such as porosity for the first time and the model parameter a that reflects the fines mode in the bi-modal breakage function increased linearly with ribblet porosity. This work demonstrates the versatility of the developed PBM and provides a systematic approach for describing the ribbon milling process.

Data on rotary die filling performance of various pharmaceutical powders.

As one of critical process steps during pharmaceutical tabletting, rotary die filling is still not well understood. To address this issue, a model rotary die filling system with a paddle feeder was developed to closely mimic the industrial process. Using this model system, the performance of various pharmaceutical powders at different turret and paddle speeds was evaluated, and the dependence of fill variation on process conditions and material properties was examined. A comprehensive dataset was created and reported here to show the effects of material and process parameters on the die filling performance and the filling consistency. It is believed that the data can also be used for data-driven process modelling and for developing robust machine learning models for pharmaceutical manufacturing.

The effects of screw-to-roll speed ratio on ribbon porosity during roll compaction.

Dry granulation through roll compaction is a technology commonly used in the pharmaceutical industry for producing roll compacted ribbons. The significance of the feed screw speed and roll speed during ribbon production was highlighted in recent publications. However, previous studies focused primarily on the individual effects of either the feed screw speed or roll speed on ribbon porosity, and the synergetic effect of these parameters was rarely examined. The aim of this study therefore was to investigate the effects of the screw-to-roll speed ratio on the porosity of roll compacted ribbons, produced at different roll compaction conditions using the microcrystalline cellulose MCC, Avicel PH-102 feed material. It was observed that ribbon porosity decreased linearly with increasing screw-to-roll speed ratio. Furthermore, an increase in the speed ratio led to an increase in the roll gap and mass throughput while a decrease in the screw constant was observed. Thus, this study demonstrates that the screw-to-roll speed ratio can be treated as one of the critical process parameters for controlling ribbon porosity and can also be used to determine the optimum operating regimes during roll compaction.

Flow behaviour of pharmaceutical powders during rotary die filling with a paddle feeder.

Rotary tabletting presses are widely used to produce tablets in the pharmaceutical industry. In the tabletting process using a rotary press, rotary die filling is one of critical process steps, as powder behaviour during die filling dictates the quality of final products, such as dosage and weight variations. It is hence of importance to understand powder flow behaviour during rotary die filling. The purpose of this study is to identify the critical process parameters and material attributes that determine the die filling performance. For this purpose, a model rotary die filling system with a paddle feeder was constructed to mimic the powder feeding process in a typical rotary press. Using this model system, the effects of powder properties, turret speed and paddle speed on die filling behaviour were investigated. Three grades of microcrystalline cellulose powders were considered. It was found that the turret speed has a more pivotal role in controlling the die filling performance than the paddle speed. In addition, it is demonstrated that powder flowability has a great impact on the fill weight variation, and a higher weight variation is induced for the powders with poorer flowability.

Spatio-temporal Index Based on Time Series of Leaf Area Index for Identifying Heavy Metal Stress in Rice under Complex Stressors.

Crops under various types of stresses, such as stress caused by heavy metals, drought and pest/disease exhibit similar changes in physiological-biochemical parameters (e.g., leaf area index [LAI] and chlorophyll). Thus, differentiating between heavy metal stress and nonheavy metal stress presents a great challenge. However, different stressors in crops do cause variations in spatiotemporal characteristics. This study aims to develop a spatiotemporal index based on LAI time series to identify heavy metal stress under complex stressors on a regional scale. The experimental area is located in Zhuzhou City, Hunan Province. The situ measured data and Sentinel-2A images from 2017 and 2018 were collected. First, a series of LAI in rice growth stages was simulated based on the WOrld FOod STudies (WOFOST) model incorporated with Sentinel 2 images. Second, the local Moran's I and dynamic time warping (DTW) of LAI were calculated. Third, a stress index based on spatial and temporal features (SIST) was established to assess heavy metal stress levels according to the spatial autocorrelation and temporal dissimilarity of LAI. Results revealed the following: (1) The DTW of LAI is a good indicator for distinguishing stress levels. Specifically, rice subjected to high stress levels exhibits high DTW values. (2) Rice under heavy metal stress is well correlated with high-high SIST clusters. (3) Rice plants subjected to high pollution are observed in the northwest of the study regions and rice under low heavy metal stress is found in the south. The results suggest that SIST based on a sensitive indicator of rice biochemical impairment can be used to accurately detect regional heavy metal stress in rice. Combining spatial-temporal features and spectral information appears to be a highly promising method for discriminating heavy metal stress from complex stressors.

Data on the drug release profiles and powder characteristics of the ethyl cellulose based microparticles prepared by the ultra-fine particle processing system.

Ethyl cellulose (EC) based microparticles (MPs) could provide sustained release for Huperzine A. The drug release mechanism of MPs was exploited to achieve an ideal drug release profile. We previously found that the wettability of MPs greatly contributed to facilitating drug release, which was detailed in a research article entitled "Huperzine A loaded multiparticulate disintegrating tablet: Drug release mechanism of ethyl cellulose microparticles and pharmacokinetic study" (Peng et al., 2019) [1]. In this article, the influence of different polymers and drugs on the drug release behavior was investigated to broaden or compensate this finding. Besides, powder characterization of MPs was used to evaluate the further application of MPs for tablets.

Developing a New Spectral Index for Detecting Cadmium-Induced Stress in Rice on a Regional Scale.

In natural farmland ecosystems, cadmium (Cd) pollution in rice has attracted increasing attention because of its high toxicity, relative mobility, and high water solubility. This study aims to develop a spectral index for detecting Cd stress in rice on a regional scale. Three experimental sites are selected in Zhuzhou City, Hunan Province. The hyperspectral data, chlorophyll (Chl) content, leaf area index, average leaf angle, Cd concentration in soil, and Sentinel-2A images from 2017 and 2018 are collected. A new spectral index sensitive to Cd stress in rice is established based on the global sensitivity analysis of the radiative transfer model PROSPECT + SAIL (commonly called PROSAIL) model with the auxiliary of the field-measured data. The heavy metal Cd stress-sensitive spectral index (HCSI) is devised as an indicator of the degree of Cd stress in rice. Results indicate that (1) the HCSI developed based on Chl is a good indicator of rice damage caused by Cd stress, that is, low values of HCSI occur in rice subject to relatively high pollution; (2) compared with common spectral indices, such as red-edge position and red-edge Chl index, HCSI is more sensitive to Chl content with higher Pearson correlation coefficients with respect to Chl content, ranging from 0.85 to 0.95; (3) HCSI is successfully applied in Sentinel-2A images from the two different years of monitoring rice Cd stress on a regional scale. Cd stress levels in rice stabilized, and the largest area percentage of each pollution levels of Cd decreased in the following order: No pollution (i.e., 40%), low pollution (i.e., 35%), and high pollution (i.e., 25%). This study indicates that a combination of simulation data from the PROSAIL model and measured data appears to be a promising method for establishing a sensitivity spectral index to heavy metal stress, which can accurately detect regional Cd stress in crops.

Evolutions of temperature and density during roll compaction of a pharmaceutical excipient.

Roll compaction is a critical unit operation in the pharmaceutical manufacture. During roll compaction, a change in the internal energy of powder due to applying of external work from the rolls can generate heat and cause an increase in the temperature of the powder, which can subsequently affect the roll compaction behaviour and the quality of ribbons. Thus, it is crucial to understand the thermal response of pharmaceutical formulations during roll compaction. This study hence aims to examine the evolution of temperature and density in powders during roll compaction. For this purpose, a systematic experimental study is performed using the peripheral quantitative computed tomography (PQCT), for the first time, and the thermographic method to investigate the thermo-mechanical behaviour of pharmaceutical powders during roll compaction. A finite element model is also developed to describe the transformation of irreversible compression work to heat as well as the energy dissipation due to the wall friction, and to predict the thermomechanical behaviour. In particular, the effect of roll speeds on the thermomechanical behaviour of powders during roll compaction is examined. It was shown that at low roll speeds, the highest temperature is reached inside of the compacted powder. As the roll speed increases, more heat is generated on the ribbon surfaces due to the powder-wall friction, while the density of ribbon deceases. It was found that the density and the temperature at the ribbon centre, were generally higher than that near to the edge, for roll compaction with fixed cheek plates.

Population balance modelling of ribbon milling with a new mass-based breakage function.

Dry granulation through roll compaction followed by milling is a widely used pharmaceutical process. The material properties of powders and the roll compaction process conditions affect the strength of ribbons, and subsequently the granule size distribution (GSD). Accurate prediction of the granule size distribution from milling of ribbons with different properties is essential for ensuring tablet quality in the final compaction stage. In this study, MCC, PH-102 ribbons with precisely controlled porosities were produced and milled in a cutting mill and granule size distribution was analysed using QicPic. A population balance model with a new breakage function based on the Weibull function was developed to model the ribbon milling process. Eight model parameters were initially obtained for each ribbon porosity and very good agreement between the model and experimental results was obtained. Sensitivity analysis was then performed and thus reduced the number of model parameters that changed with ribbon porosity to two in the breakage function. The refined model was able to predict the granule size distribution both within and outside the experimental boundaries. It was shown that the model developed in this study has a great potential for predicting granule properties and therefore the optimisation of the dry granulation process.

Piezoelectric Shunt Stiffness in Rhombic Piezoelectric Stack Transducer with Hybrid Negative-Impedance Shunts: Theoretical Modeling and Stability Analysis.

Negative-capacitance shunted piezoelectric polymer was investigated in depth due to its considerable damping effect. This paper discusses the novel controlled stiffness performance from a rhombic piezoelectric stack transducer with three hybrid negative-impedance shunts, namely, negative capacitance in series with resistance, negative capacitance in parallel with resistance, and negative inductance/negative capacitance (NINC) in series with resistance. An analytical framework for establishing the model of the coupled system is presented. Piezoelectric shunt stiffness (PSS) and piezoelectric shunt damping (PSD) are proposed to analyze the stiffness and damping performances of the hybrid shunts. Theoretical analysis proves that the PSS can produce both positive and negative stiffness by changing the negative capacitance and adjustable resistance. The Routh-Hurwitz criterion and the root locus method are utilized to judge the stability of the three hybrid shunts. The results point out that the negative capacitance should be selected carefully to sustain the stability and to achieve the negative stiffness effect of the transducer. Furthermore, negative capacitance in parallel with resistance has a considerably better stiffness bandwidth and damping performance than the other two shunts. This study demonstrates a novel electrically controlled stiffness method for vibration control engineering.

Unified size-density and size-topology relations in random packings of dry adhesive polydisperse spheres.

We study the size-density and size-topology relations in random packings of dry adhesive polydisperse microspheres with Gaussian and lognormal size distributions through a geometric tessellation. We find that the dependence of the neighbor number on the centric particle size is always quasilinear, regardless of the size distribution, size span, or interparticle adhesion. The average local packing fraction as a function of normalized particle size for different size variances is well regressed on the same profile, which increases to larger values as the relative strength of adhesion decreases. The variations of the local coordination number with the particle size converge onto a single curve for all adhesive particles, but gradually transfer to another branch for nonadhesive particles. Such adhesion-induced size-density and size-topology relations are interpreted theoretically with a modified geometrical "granocentric" model, where the model parameters are dependent on a single dimensionless adhesion number. Our findings, together with the modified theory, provide a more unified perspective on the substantial geometry of amorphous polydisperse systems, especially those with fairly loose structures.

A Novel PZT Pump with Built-in Compliant Structures.

Different to the traditionally defined valved piezoelectric (PZT) pump and valveless PZT pump, two groups of PZT pumps with built-in compliant structures-with distances between the free ends of 0.2 mm (Group A) and 0 mm (Group B)-were designed, fabricated, and experimentally tested. This type of pump mainly contains a chamber 12 mm in diameter and 1.1 mm in height, a PZT vibrator, and two pairs of compliant structures arranged on the flowing channel. The flow-resistance differences between these two groups of PZT pumps were theoretically and experimentally verified. The relationships between the amplitude, applied voltage and frequency of the PZT vibrators were obtained experimentally, with results illustrating that the amplitude linearly and positively correlates with the voltage, while nonlinearly and negatively correlating to the frequency. The flow rate performance of these two groups was experimentally tested from 110⁻160 Vpp and 10⁻130 Hz. Results showed that the flow rate positively correlates to the voltage, and the optimum flow rate frequency centers around 90 Hz for Group A and 80 Hz for Group B, respectively. The flow rate performances of Group B were further measured from 60⁻100 Hz and 170⁻210 Vpp, and obtained optimal flow rates of 3.6 mL/min at 210 Vpp and 80 Hz when ignoring the siphon-caused backward flow rate. As the compliant structures are not prominently limited by the channel's size, and the pump can be minimized by Micro-electromechanical Systems (MEMS) processing methods, it is a suitable candidate for microfluidic applications like closed-loop cooling systems and drug delivery systems.