The influence of orifice height on flow rate of powder excipients

The influence of the orifice height of a cylindrical, flat-bottomed hopper on the mass flow rate of the free-flowable size fractions of sodium chloride and boric acid was investigated. It was observed that a zone of sudden acceleration of the mass flow under gravity occurred when a critical orifice height had been achieved. Based on the results, an orifice diameter equal to 12 mm with a height of between 8-16 mm is recommended for the faster flow of sodium chloride while an orifice diameter equal to 8 mm with a height of less than 8mm is appropriate for the slower flow of boric acid. In summary, the orifice height should be taken into consideration as an important parameter of a cylindrical test hopper in order to obtain a reproducible and comparable mass flow as the single-point characteristic of powder flowability.     

Indentation Test for Free-Flowable Powder Excipients

Indentation of a sphere into nonconsolidated powder excipients is a suitable complementary method for the evaluation of flow properties of the free-flowable noncohesive powders. To use the standard penetrometry method to indentation of nonconsolidated powder layer by a glass sphere of 16 mm in diameter, the suitable geometry of the measurement container is required to prevent undesirable moving in a direction opposite to that in which the indenting sphere moves. Thus, the powder indentation by a sphere seems to be similar to indentation by the Brinell hardness tester. In this work, the depth of indentation was measured for five pharmaceutical powder excipients: sodium chloride, sodium citrate, potassium citrate, sorbitol, and boric acid with the three size fractions in the range of 0.315–0.630 mm. To express powder flowability, the uniform mass and/or volume flow rate from the 10-mm cylindrical outlet of the cylindrical testing hopper was used. The relationships between the powder flow rate and its bulk density and/or the different characteristics of indentation were modeled by using linear regression. Out of the indentation characteristics, the mass of indentation calculated as the multiple of the volume of indentation and the powder bulk density could be recommended to estimate the powder mass flow rate due to the linear regression with the coefficient of determination equal to 0.973 and the accuracy of 4.3%. In conclusion, the indentation by the sphere could be recommended as a quick simple method for the comparison of flow properties of the nonconsolidated, noncohesive powder excipients.     

Flow rate of some pharmaceutical diluents through die-orifices relevant to mini-tableting

The effects of cylindrical orifice length and diameter on the flow rate of three commonly used pharmaceutical direct compression diluents (lactose, dibasic calcium phosphate dihydrate and pregelatinised starch) were investigated, besides the powder particle characteristics (particle size, aspect ratio, roundness and convexity) and the packing properties (true, bulk and tapped density). Flow rate was determined for three different sieve fractions through a series of miniature tableting dies of different orifice diameter (0.4, 0.3 and 0.2 cm) and thickness (1.5, 1.0 and 0.5 cm). It was found that flow rate decreased with the increase of the orifice length for the small diameter (0.2 cm) but for the large diameter (0.4 cm) was increased with the orifice length (die thickness). Flow rate changes with the orifice length are attributed to the flow regime (transitional arch formation) and possible alterations in the position of the free flowing zone caused by pressure gradients arising from the flow of self-entrained air, both above the entrance in the die orifice and across it. Modelling by the conventional Jones-Pilpel non-linear equation and by two machine learning algorithms (lazy learning, LL, and feed-forward back-propagation, FBP) was applied and predictive performance of the fitted models was compared. It was found that both FBP and LL algorithms have significantly higher predictive performance than the Jones-Pilpel non-linear equation, because they account both dimensions of the cylindrical die opening (diameter and length). The automatic relevance determination for FBP revealed that orifice length is the third most influential variable after the orifice diameter and particle size, followed by the bulk density, the difference between bulk and tapped densities and the particle convexity.     

Developing a Virtual Flowability Sensor for Monitoring a Pharmaceutical Dry Granulation Line

Current technologies to measure granule flowability involve at-line methods that can take hours to perform. This is problematic for a continuous dry granulation tableting line, where the quality assurance and control of the final tablet products depend on real-time monitoring and control of powder flowability. Hence, a real-time alternative is needed for measuring the flowability of the granular products coming out of the roller compactor, which is the unit operation immediately preceding the tablet press. Since particle analyzers have the potential to take inline measurements of the size and shape of granules, they can potentially serve as real-time flowability sensors, given that the size and shape measurements can be used to reliably predict flowability measurements.This paper reports on the use of Partial Least Squares (PLS) regression to utilize distributions of size and shape measurements in predicting the output of three different types of flowability measurements: rotary drum flow, orifice flow, and tapped density analysis. The prediction performance of PLS had a coefficient of determination ranging from 0.80 to 0.97, which is the best reported performance in the literature. This is attributed to the ability of PLS to handle high collinearity in the datasets and the inclusion of multiple shape characteristics—eccentricity, form factor, and elliptical form factor—into the model. The latter calls for a change in industry perspective, which normally dismisses the importance of shape in favor of size; and the former suggests the use of PLS as a better way to reduce the dimensionality of distribution datasets, instead of the widely used practice of pre-selecting distribution percentiles.     

Effects of Water on Powder Flowability of Diverse Powders Assessed by Complimentary Techniques

The storage of bulk powders in suboptimal conditions can affect their handling, processing, and performance. The aim of this work was to assess the influence of storage conditions on powder flowability, which is a crucial property in powder processing. The 7 model compounds were common tablet excipients with varying crystallinity ranging from amorphous to partially crystalline, and 2 crystalline materials. The water sorption-desorption isotherms of all the excipients were analyzed with dynamic vapor sorption, and the kinetics of the water sorption at 75% relative humidity were investigated using isothermal microcalorimetry. In addition, the powders were conditioned at 3 relative humidities 23%, 43%, and 75% at ambient temperature, and their flowability was measured using 3 different techniques: ring shear testing, basic flowability energy, and flow through an orifice. All 3 methods were able to detect the storage-related change in flowability induced by varying storage conditions. With increasing storage humidity, a trend toward a decrease in powder flowability could be detected with the chosen instruments. Furthermore, the same rank order of powder flowability could be observed using the flow through an orifice and ring shear testing method.     

Indentation test for free-flowable powder excipients

Indentation of a sphere into nonconsolidated powder excipients is a suitable complementary method for the evaluation of flow properties of the free-flowable noncohesive powders. To use the standard penetrometry method to indentation of nonconsolidated powder layer by a glass sphere of 16 mm in diameter, the suitable geometry of the measurement container is required to prevent undesirable moving in a direction opposite to that in which the indenting sphere moves. Thus, the powder indentation by a sphere seems to be similar to indentation by the Brinell hardness tester. In this work, the depth of indentation was measured for five pharmaceutical powder excipients: sodium chloride, sodium citrate, potassium citrate, sorbitol, and boric acid with the three size fractions in the range of 0.315-0.630 mm. To express powder flowability, the uniform mass and/or volume flow rate from the 10-mm cylindrical outlet of the cylindrical testing hopper was used. The relationships between the powder flow rate and its bulk density and/or the different characteristics of indentation were modeled by using linear regression. Out of the indentation characteristics, the mass of indentation calculated as the multiple of the volume of indentation and the powder bulk density could be recommended to estimate the powder mass flow rate due to the linear regression with the coefficient of determination equal to 0.973 and the accuracy of 4.3%. In conclusion, the indentation by the sphere could be recommended as a quick simple method for the comparison of flow properties of the nonconsolidated, noncohesive powder excipients.     

Gas-pressurized dispersive powder flow tester for low volume sample characterization

The conventional powder flow testers require sample volumes larger than 40 g and are met with experimental hiccups due to powder cohesion. This study designed a gas-pressurized dispersive powder flow tester where a high velocity air is used to disaggregate powder (9 g) and eliminate its cohesion. The pressurized gas entrained solid particles leaving an orifice where the distance, surface area, width and weight of particle dispersion thereafter are determined as flow index. The flow indices of seven lactose grades with varying size, size distribution, shape, morphology, bulk and tapped densities characteristics were examined. They were compared against Hausner ratio and Carr's index parameters of the same powder mass. Both distance and surface area attributes of particle dispersion had significant negative correlations with Hausner ratio and Carr's index values of lactose. The distance, surface area and ease of particle dispersion varied proportionately with circular equivalent, surface weighted mean and volume weighted mean diameters of lactose, and inversely related to their specific surface area and elongation characteristics. Unlike insensitive Hausner ratio and Carr's index, an increase in elongation property of lactose particles was detectable through reduced powder weight loss from gas-pressurized dispersion as a result of susceptible particle blockage at orifice. The gas-pressurized dispersive tester is a useful alternative flowability measurement device for low volume and cohesive powder.     

Impact of Shear History on Powder Flow Characterization Using a Ring Shear Tester

In this study, we have investigated the impact of repeated shear displacement on powder flow properties. We show that when multiple yield loci are obtained using the same bulk solid specimen by stepping through different stress levels (i.e., stress walk [SW]), the shear deformation of the powder in a rotational shear cell, that is, Schulze Ring Shear Tester, is maximized, reducing the powder shear strength. This approach is material and time sparing; however, it imprecisely predicts better powder flowability. The magnitude of the change in the unconfined yield strength, σ_c, due to this prolonged shear displacement appears to be material-dependent, being less impactful for free-flowing powders. Using the SW and the individual yield loci-generated flow properties, we have demonstrated that in hopper design, the shear displacement effect impacts the computed critical arching diameter more than the critical mass flow angle. This knowledge of powder flow properties highlights limitations associated with the SW. An exponential function was found to describe the relationship between the change in σ_c at the highest major principal stress and the density weighted flowability, ff_ρ, with an R² of 0.98. Such a model could be a valuable tool for correcting shear strength results obtained from SW, saving time, and material.     

Cooling as a possible method for increasing the flowability of certain pharmaceutical and other powders

Measurements have been made of the rates of flow under gravity of powdered sugars and of fatty acids through circular orifices at temperatures between ?25 and 110 °C. The flow rates decrease considerably as the powders are heated; conversely they increase as the powders are cooled from a high ambient temperature of 40 to ?25 °C. The results are ascribed to changes in the cohesiveness of the powders caused by softening and plastic deformation of particles at elevated temperatures. Lactose, paracetamol and griseofulvin granule formulations have been reported to show similar effects and the possibility is discussed of using cooling to increase the flowability of particular powders in pharmaceutical production. The rates of flow of the powders are given by the expression where W is the flow rate in g min^?1, Do is the orifice diameter in cm, ρ is the particle density in g cm^?3, g is the gravitational constant, and A and n are numerical terms which depend on temperature and particle size.     

Design and validation of an annular shear cell for pharmaceutical powder testing

An annular shear cell was constructed for powder flow testing, the influence of design and process parameters was characterized, and the results were compared with other flow methods. The shear cell was designed with interchangeable parts to mimic other shear cells. The texture of the powder-metal interface and the gap distance between the lid and side wall of the trough were varied, and the effects of shear rate, powder bed thickness, and consolidation times were tested. Shear parameters, such as cohesion, angles of friction, and flow factors, were measured for microcrystalline cellulose, anhydrous lactose, spray-dried lactose, mannitol, dibasic calcium phosphate dihydrate, anhydrous theophylline, and theophylline monohydrate powder. The results were then compared with the Carr index, mass flow rate, and flowability index. Design parameters such as surface texture and the gap distance significantly affected the shear call results, whereas for the process parameters studied, the shear rate, consolidation time, and powder bed height had a minimal effect on the shear cell results. Of the shear parameters obtained, the angles of friction best represented the known flow properties of powders and were in general agreement with those from other flow tests.     

Flow rates of granular materials through moving orifices

An apparatus is described which will measure the flow of powder through a moving orifice (die). It is shown that this type of flow, denoted dynamic flow, differs in some respects from static flow, i.e. flow through a stationary orifice. In other respects, e.g. the relation of flow to orifice diameter, the relations found in dynamic flow are similar to the ones reported for static flow. The results are treated in such a fashion that extrapolations to speeds encountered in high speed tablet presses can be made.     

Cooling as a possible method for increasing the flowability of certain pharmaceutical and other powders

Measurements have been made of the rates of flow under gravity of powdered sugars and of fatty acids through circular orifices at temperatures between -25 and 110 degrees C. The flow rates decrease considerably as the powders are heated; conversely they increase as the powders are cooled from a high ambient temperature of 40 to -25 degrees C. The results are ascribed to changes in the cohesiveness of the powders caused by softening and plastic deformation of particles at elevated temperatures. Lactose, paracetamol and griseofulvin granule formations have been reported to show similar effects and the possibility is discussed of using cooling to increase the flowability of particular powders in pharmaceutical production. The rates of flow of the powders are given by the expression(formula: see text)where W is the flow rate in g min-1, Do is the orifice diameter in cm, rho is the particle density in g cm-3, g is the gravitational constant, and A and n are numerical terms which depend on temperature and particle size.     

Effect of Geometric Structure of Flow Promoting Agents on the Flow Properties of Pharmaceutical Powder Mixture

Purpose. The object of this work was to investigate the mechanism of how the surface geometric structure of flow agents affects on the flowability of pharmaceutical powder mixtures. Methods. Nonporous and porous silicas were mixed with directly compressible fillers as flow promoting agents. The geometric structure of flow agents was investigated by gas adsorption and laser diffraction analysis. Flowability was evaluated with Carr's index measurement. Adhesion force between fillers and flow agents was determined using atomic force microscopy. Results. Flowability was improved with the addition of both nonporous and porous flow agents. In the case of nonporous flow agents, effect to promote flowability decreased with the increase of particle diameter, whereas porous flow agents highly improved flowability independent of particle diameter. Atomic force microscopy measurement found that the adhesion force between a porous agent and filler was smaller than that between a nonporous agent and filler. Conclusions. Enhancement of flowability varies depending on the geometric structure of flow agents. Porous flow agents improve flow properties more than nonporous agents, because porosity is highly contributed to reduction of adhesion force between particles.     

Real-Time Monitoring of Powder Mass Flowrates for Plant-Wide Control of a Continuous Direct Compaction Tablet Manufacturing Process

While measurement and monitoring of powder/particulate mass flow rate are not essential to the execution of traditional batch pharmaceutical tablet manufacturing, in continuous operation, it is an important additional critical process parameter. It has a key role both in establishing that the process is in a state of control, and as a controlled variable in process control system design. In current continuous tableting line operations, the pharmaceutical community relies on loss-in-weight feeders to monitor and understand upstream powder flow dynamics. However, due to the absence of established sensing technologies for measuring particulate flow rates, the downstream flow of the feeders is monitored and controlled using various indirect strategies. For example, the hopper level of the tablet press is maintained as a controlled process output by adjusting the turret speed of the tablet press, which indirectly controlling the flow rate. This gap in monitoring and control of the critical process flow motivates our investigation of a novel PAT tool, a capacitance-based sensor (ECVT), and its effective integration into the plant-wide control of a direct compaction process. First, the results of stand-alone experimental studies are reported, which confirm that the ECVT sensor can provide real-time measurements of mass flow rate with measurement error within -1.8 ~ 3.3% and with RMSE of 0.1 kg/h over the range of flow rates from 2 to 10 kg/h. The key caveat is that the powder flowability has to be good enough to avoid powder fouling on the transfer line walls. Next, simulation case studies are carried out using a dynamic flowsheet model of a continuous direct compression line implemented in Matlab/Simulink to demonstrate the potential structural and performance advantages in plant-wide process control enabled by mass flow sensing. Finally, experimental studies are performed on a direct compaction pilot plant in which the ECVT sensor is located at the exit of the blender, to confirm that the powder flow can be monitored instantaneously and controlled effectively at the specified setpoint within a plant-wide feedback controller system.     

Effect of moisture and magnesium stearate concentration on flow properties of cohesive granular materials

In this article the gravitational displacement rheometer (GDR) is used to characterize the effects of formulation composition and environmental conditions (moisture) on flow properties of cohesive pharmaceutical powders under unconfined conditions. The amount of moisture in the sample often has important effects on the physical and chemical properties of pharmaceutical solids. Properties such as flow, compaction, disintegration, dissolution, hardness and chemical stability are all influenced by moisture. In the case of lactose, as moisture content increases in the powder bed, the flowability becomes poorer as the moisture condenses on the surface and increases cohesion. The celluloses show opposite effect as compared to lactose. Here, as moisture content increases, the flow properties improve dramatically. The GDR also captures the effect of lubricant concentration on the cohesion of powders. The presence of lubricant does not play any significant impact for free flowing powders, but as powder cohesion increases, the lubricants allow for improved flowability of powders. The GDR was also used for a case study of real drug formulation. The methodology was able to evaluate the impact of humidity and lubricant concentration on the flow properties of the formulation.     

In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices.

Experiments were performed to determine the effect of different pharmaceutical aerosol inhalation devices on the deposition of monodisperse aerosols in an idealized mouth and throat geometry. The devices included two dry powder inhalers (Diskus and Turbuhaler), two nebulizers (Pari LC STAR and Hudson T-Updraft), and a metered dose inhaler with attached holding chamber (Aerochamber), in addition to a straight tube (1.7 cm inner diameter). Aerosol particles (DL-alpha tocopheryl acetate) of diameters of 2.5, 5, and 7 microm generated by a vibrating orifice generator were inhaled at steady air flow rates of Q = 5-90 L/min through the devices and into the mouth-throat. Deposition in the mouth-throat and after-filter were determined by ultraviolet (UV) spectrophotometric assay. The amount of deposition in the mouth and throat region was found to depend on the type of device that the aerosol entered through. Deposition in the extrathoracic region with the two types of jet nebulizers did not differ significantly (p > 0.1) from that of a straight tube or each other over their entire tested range of 590 > or = pd2Q > or = 11,375, where p is particle density (in g/cm3), d is particle diameter (in microm), and Q is flow rate (in cm3/s). The metered dose inhaler with attached holding chamber was found to differ from the straight tube only at two intermediate values of pd2Q = 5,145 and 16,033. The deposition occurring for the dry powder inhalers was found to be significantly greater than for the straight tube for all values of pd2Q > or = 10,954 for the Diskus and pd2Q > or = 9,435 for the Turbuhaler. Deposition with the dry powder inhalers was found to be up to 14 times greater than that with the straight tube. Thus, the inhaler geometry that the aerosol passes through prior to entering the mouth and throat region can greatly affect the deposition in the mouth-throat.     

Evaluation of Small-Scale Powder Flow Characterization Tests in the Prediction of Large-Scale Process Failures

In pharmaceutical development, powder flow characteristics are notoriously difficult to predict. Although tests exist that aim to determine the flowability of powders, many have not been definitively correlated with a powder’s performance in downstream processes. Part of the challenge is that powder flow must occur over a broad range of consolidating stresses, including low-stress flow regimes such as the filling of a die cavity in a tablet press and high-stress flow regimes such as the deformation associated with tablet compression. The objective of this work was to characterize several placebo formulations utilizing a variety of standardized and non-standardized experiments and contrasting those results with downstream tablet compression performance. Angle of repose, bulk and tap density, Hausner ratio, Carr’s compressibility index, a visual powder flow assessment, a mass flow rate test, Flodex, and powder shear testing were evaluated on several different blends of placebo powders to determine a predictive test for downstream process performance. The placebo powders consisted of a standard base unit formula, mixed with various levels of four different “pseudo-active pharmaceutical ingredients (APIs)” (i.e., excipients that mimic poorly flowing active pharmaceutical ingredients). All formulations were evaluated by the individual flow tests and then compressed on a rotary tablet press. Formulations were deemed failures if the relative standard deviation of tablet weight was >2 %, material stuck to punches (low lubrication), or exhibited ejection forces high enough to trigger automatic shutdown of tablet press. The 2 % RSD limit is based on internally developed best practices for transferring tablet compression processes from development into manufacturing. The results of the tablet compression process were then compared to the results of the flowability tests to detect any correlations. The Hausner ratio and powder shear test results discriminated marginally between successful and failed batches and were highly correlated with each other.     

Roller compaction of crude plant material: influence of process variables, polyvinylpyrrolidone, and co-milling

Roller compaction of a milled botanical (Baphicacanthus cusia) with and without a binder, polyvinylpyrrolidone (PVP) was conducted. Effects of co-milling on binder function and flowability of the powder blend was also investigated. Flakes were comminuted, and the size and size distribution, friability, Hausner ratio, and Carr index of the granulations were determined. Crude herb should be reduced to a suitable size for it to be successfully roller compacted. Larger-sized and less friable granules were obtained with decreasing roller speed. Addition of PVP affected the flowability and binding capacity of the herbal powder blend, which influenced size and friability of the granules. Co-milling of PVP with the herbal powder enhanced the flow of the blends and the effectiveness of the binder, which contributed favorably to the roller-compacted product. Roller compaction is a convenient and cost-effective granulating technique suitable for milled botanicals. Co-milling can be used to improve the properties of roller-compacted products.     

Advancing Pharmaceutical Dry Milling by Process Analytics and Robustness Testing

The objectives of this work were to implement on-line dynamic image analysis and to introduce a novel at-line flowability analyzer in pharmaceutical dry milling. We used a pilot-scale conical mill and flowability of a placebo granulate was monitored using a powder avalanching analyzer. Experiments were designed and evaluated by means of response surface methodology in conjunction with robustness testing. The process parameters impeller speed and screen size significantly affected the particle size distribution and flow rate of the milled granules. Feeder speed did not affect the particle size, but displayed a statistically significant influence on the flow responses. Robustness testing was able to capture the effect of noise factors on the responses and showed clear differences between different lots of the placebo granulate in addition to temperature-dependent changes in flow behavior. Thus, on-line dynamic image analysis and at-line flowability characterization, together as complementary process analytical tools, provided valuable information. The combined analysis was of particular interest for testing the process and noise factors so that future process development can profit from this advancement in dry milling.     

Penetrometry and estimation of the flow rate of powder excipients

In this work, penetrometry with a sphere was employed to study the flow properties of non-consolidated pharmaceutical powder excipients: sodium chloride, sodium citrate, boric acid, and sorbitol. In order to estimate flow rate, the pressure of penetration in Pascals was used. Penetrometry measurement with a sphere requires modification of the measurement container, in particular by decreasing the diameter of the container, to prevent undesirable movement of material in a direction opposite to that in which the sphere penetrates. Thus penetrometry by a sphere seems to be similar to indentation by the Brinell hardness tester. The pressure of penetration was determined from the depth of penetration by analogy with the Brinell hardness number and an equation for the inter conversion of the two variables is presented. The penetration pressure allowed direct estimation of the flow rate only for those powder excipients with a size fraction in the range of 0.250-0.630 mm. Using the ratio of penetration pressure to bulk density, a polynomial quadratic equation was generated from which the flow rates for the group of all tested powders could be estimated. Finally, if the inverse ratio of bulk density and penetration pressure was used as an independent variable, the flow rate could be estimated by linear regression with the coefficient of determination r2 = 0.9941. In conclusion, using sphere penetrometry, the flow properties of non-consolidated powder samples could be investigated by indentation. As a result, a linear regression in which the flow rate was directly proportional to the powder bulk density and inversely proportional to the penetration pressure could be best recommended for the estimation of the flow rate of powder excipients.