An experimental study on flow behaviour of pharmaceutical powders during suction filling.

Die filling is a crucial step in the pharmaceutical tablet manufacturing process. For industrial-scale production using rotary presses, suction filling is typically employed due to its significant efficiency advantages over gravity filling. Despite its widespread use, our understanding of the suction filling process remains limited. Specifically, there is insufficient comprehension of how filling performance is influenced by factors such as suction velocity, filling velocity, and the properties of the powder materials. Building on our previous research, this study aims to further investigate the effects of powder properties and process parameters (e.g., filling velocity, suction velocity, fill depth) on suction filling behaviour. A systematic experimental investigation was conducted using a model suction filling system, considering both cohesive and free-flowing pharmaceutical powders. The effect of fill depth on suction filling of these powders was examined at different filling and suction velocities. The results demonstrate that two distinctive flow regimes for suction filling can be identified: slow filling and fast filling. These regimes are delineated by a critical filling-to-suction velocity ratio. In the slow filling regime, the filling-to-suction velocity ratio is lower than the critical ratio, meaning that the filling phase is slower than the suction phase. Conversely, the fast filling regime occurs when the filling-to-suction velocity ratio exceeds the critical ratio, implying that the filling phase is faster than the suction phase. This study reveals, for the first time, that when the powder flow pattern during suction filling is dominated by plug flow, full die fill (i.e., the fill ratio equals unity) is achieved in the slow filling regime. However, in the fast filling regime, incomplete die fill is obtained. It is also found that when plug flow prevails during fast filling, the fill ratio has an inverse correlation with the filling-to-suction velocity ratio. This study further reveals that when the plug flow assumption is valid, the filling ratio at various fill-to-suction velocity ratios can be well predicted mathematically. Furthermore, it is also found that once the powder flow pattern differs from the ideal plug flow, which could be induced by the filling conditions and powder cohesion, the fill ratio can be overpredicted.

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.

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.

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.

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.

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.

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.

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.

Experimental Study on the Performance of Hydraulic Vibration Assisted Broaching (HVAB) Based on Piezoelectric Sensors.

In order to improve the keyway broaching process and verify the feasibility of vibration-assisted broaching process, an experimental study on a novel hydraulic vibration assisted broaching (HVAB) system with double-valve electro-hydraulic exciter (DVEHE) is proposed in this paper. The performances of HVAB at different excitation frequencies were compared from three aspects: (a) the cutting force under the different vibration frequencies, (b) the surface roughness of the workpiece, and (c) the flank face wear of the tool. For precision on-line measurement of larger broaching forces, four piezoelectric sensors were fixed on the broaching machine. The experimental results show that HVAB can effectively improve the performance of the broaching process, approximately reduce the broaching force by as much as 9.7% compared to conventional broaching (CB) and improve the surface quality of workpiece. Some explanations are offered to support the observations.

A liquid crystalline precursor incorporating chlorhexidine acetate and silver nanoparticles for root canal disinfection.

Lyotropic liquid crystals (LLC) have received increasing attention as a drug delivery system. In this study, a novel intra-canal disinfectant based on the glycerol monooleate (GMO) LLC precursor incorporation with chlorhexidine (CHX) and silver nanoparticles (Ag-NPs) was designed and evaluated. The LLC precursor with excellent fluidity was able to penetrate deeply into the complex tiny collateral branch root canals. The transformation of cubic LLC in root canals upon coming into contact with water provided long-lasting disinfection against multidrug-resistant bacteria to avoid the endodontic reinfection and follow-up visits. The GMO-ethanol-water (48% : 12% : 40%, w/w) formulation containing 0.5% CHX and 0.02% Ag-NPs was selected for further studies. The low viscosity of the precursor presented excellent injectability and flowabilities. From the in vitro release test, the release behaviours were found to be influenced by CHX and Ag-NP contents, allowing the optimized precursor to obtain a 28-day release profile. The CHX-Ag-NP containing LLC precursor exhibited an excellent and sustained sterilization effect on Enterococcus faecalis for more than one month with a bacterial inactivation rate of ≥98.5%, which was far more than the minimum clinical requirement (7 days). Furthermore, no in vitro toxicity was observed in the cytotoxicity evaluation. The CHX-Ag-NP containing LLC precursor was proved to be a promising intra-canal disinfectant in our study.

Supersaturable solid self-microemulsifying drug delivery system: precipitation inhibition and bioavailability enhancement.

Solid self-emulsifying drug delivery system (SSEDDS), which incorporates liquid SEDDS into a solid dosage form, has been recently introduced to improve the oral bioavail-ability of poorly water-soluble drugs. However, supersaturated drug generated by SSEDDS is thermodynamically unstable and tends to precipitate rapidly prior to absorption, resulting in compromised bioavailability. The aim of this study was to construct a novel supersaturated SSEDDS (super-SSEDDS) by combining SSEDDS with appropriate precipitation inhibitor. Fenofibrate (FNB), a sparingly soluble drug, was selected as a model drug in this study. An optimized SSEDDS was prepared by solvent evaporation by using mesoporous silica Santa Barbara Amorphous-15 as the inert carrier. Supersaturation assay was conducted to evaluate the precipitation inhibition capacity of different polymers, and the results showed that Soluplus® could retard the FNB precipitation more effectively and sustain a higher apparent concentration for ~120 min. This effect was also clearly observed in the dissolution profiles of FNB from SSEDDS under supersaturated condition. The study of the mechanism suggested that the inhibition effect might be achieved both thermodynamically and kinetically. The area under the concentration-time curve of the super-SSEDDS was 1.4-fold greater than that of SSEDDS in the absence of Soluplus, based on an in vivo pharmacokinetic study conducted in beagle dogs. This study has demonstrated that the approach of combining SSEDDS with Soluplus as a supersaturation stabilizer constitutes a potential tool to improve the absorption of poorly water-soluble drugs.

Thermal properties of compacted pharmaceutical excipients.

Thermal properties of powders are critical material attributes that control temperature rise during tableting and roll compaction. In this study, various analytical methods were used to measure the thermal properties of widely used pharmaceutical excipients including microcrystalline cellulose (MCC) of three different grades (Avicel PH 101; Avicel PH 102 and Avicel DG), lactose and mannitol. The effect of relative density on the measured thermal properties was investigated by compressing the powders into specimen of different relative densities. Differential thermal analysis (DTA) was employed to explore endothermic or exothermic events in the temperature range endured during typical pharmaceutical manufacturing processes, such as tabletting and roll compaction. Thermogravimetric analysis (TGA) was performed to analyse the water/solvent content, either in the form as solvates or as loosely bound molecules on the particle surface. Thermal conductivity analysis (TCA) was conducted to measure thermal conductivity and volumetric heat capacity. It is shown that, for the MCC powders, almost no changes in morphology or structural changes were observed during heating to temperatures up to 200°C. An increase in relative density or temperature leads to a high thermal conductivity and the volumetric heat capacity. Among all MCC powders considered, Avicel DG showed the highest increase in thermal conductivity and the volumetric heat capacity, but this heat capacity was not sensitive to the measurement temperature. For lactose and mannitol, some endothermic events occurred during heating. The thermal conductivity increased with the increase in temperature and relative density. A model was also developed to describe the variation of the thermal conductivity and the volumetric heat capacity with the relative density and the temperature. It was shown that the empirical model can well predict the dependency of the thermal conductivity and the volumetric heat capacity on the relative density and the temperature.

The Effects of Relative Humidity on the Flowability and Dispersion Performance of Lactose Mixtures.

The flowability and dispersion behavior are two important physicochemical properties of pharmaceutical formulations for dry powder inhalers (DPIs). They are usually affected by the environmental conditions, such as temperature and relative humidity (RH). However, very few studies have been focused on the relationship between the two properties and their dependence on RH during storage. In this research, model pharmaceutical formulations were prepared using mixtures of coarse and fine lactose. The fractions of fines in the mixtures were 0%, 5%, 10%, and 20%, respectively. These blends were stored at four different RH levels, 0%, 30%, 58%, and 85%, for 48 h. The FT4 Powder Rheometer was used to evaluate the powder flowability, and the Malvern Spraytec® laser diffraction system was employed to assess the powder dispersion performance. The results indicated that both the flow and dispersion properties of lactose blends deteriorate after being stored at 85% RH, but improved after being conditioned at 58% RH. The fine particle fractions (FPFs) of the blends with 5% and 10% fine fractions and the as-received coarse lactose decreased when they were conditioned at 30% RH. For the blend with 20% fine fraction, a high RH during storage (i.e., 85% RH) affected the dispersion property, but had a limited influence on its flowability, while, for the coarse lactose powder, the different RH conditions affected its flowability, but not the dispersion results. A strong correlation between the powder flowability and its dispersion performance was found.

On Identification of Critical Material Attributes for Compression Behaviour of Pharmaceutical Diluent Powders.

As one of the commonly-used solid dosage forms, pharmaceutical tablets have been widely used to deliver active drugs into the human body, satisfying patient's therapeutic requirements. To manufacture tablets of good quality, diluent powders are generally used in formulation development to increase the bulk of formulations and to bind other inactive ingredients with the active pharmaceutical ingredients (APIs). For formulations of a low API dose, the drug products generally consist of a large fraction of diluent powders. Hence, the attributes of diluents become extremely important and can significantly influence the final product property. Therefore, it is essential to accurately characterise the mechanical properties of the diluents and to thoroughly understand how their mechanical properties affect the manufacturing performance and properties of the final products, which will build a sound scientific basis for formulation design and product development. In this study, a comprehensive evaluation of the mechanical properties of the widely-used pharmaceutical diluent powders, including microcrystalline cellulose (MCC) powders with different grades (i.e., Avicel PH 101, Avicel PH 102, and DG), mannitol SD 100, lactose monohydrate, and dibasic calcium phosphate, were performed. The powder compressibility was assessed with Heckel and Kawakita analyses. The material elastic recovery during decompression and in storage was investigated through monitoring the change in the dimensions of the compressed tablets over time. The powder hygroscopicity was also evaluated to examine the water absorption ability of powders from the surroundings. It was shown that the MCC tablets exhibited continuous volume expansion after ejection, which is believed to be induced by (1) water absorption from the surrounding, and (2) elastic recovery. However, mannitol tablets showed volume expansion immediately after ejection, followed by the material shrinkage in storage. It is anticipated that the expansion was induced by elastic recovery to a limited extent, while the shrinkage was primarily due to the solidification during storage. It was also found that, for all powders considered, the powder compressibility and the elastic recovery depended significantly on the particle breakage tendency: a decrease in the particle breakage tendency led to a slight decrease in the powder compressibility and a significant drop in immediate elastic recovery. This implies that the particle breakage tendency is a critical material attribute in controlling the compression behaviour of pharmaceutical powders.