Residence Time Distribution Profiles Research Articles

Statistical data treatment for residence time distribution studies in pharmaceutical manufacturing

Residence time distribution (RTD) method has been widely used in the pharmaceutical manufacturing for understanding powder dynamics within unit operations and continuous integrated manufacturing lines. The dynamics thus captured is then used to develop predictive models for unit operations and important RTD-based applications ensuring product quality assurance. Despite thorough efforts in tracer selection, data acquisition, and calibration model development to obtain tracer concentration profiles for RTD studies, there can exist significant noise in these profiles. This noise can make it challenging to identify the underlying signal and get a representative RTD of the system under study. Such concerns have previously indicated the importance of noise handling for RTD measurements in literature. However, the literature does not provide sufficient information on noise handling or data treatment strategies for RTD studies. To this end, we investigate the impact of varying levels of noise using different tracers on measurement of RTD profile and its applications. We quantify the impact of different denoising methods (time and frequency averaging methods). Through this investigation, we see that Savitsky Golay filtering turns out to a good method for denoising RTD profiles despite varying noise levels. The investigation is performed such that the key features of the RTD profile (which are important for RTD based applications) are preserved. Subsequently, we also investigate the impact of denoising on RTD-based applications such as out-of-specification (OOS) analysis and RTD modeling. The results show that the degree of noise levels considered in this work do not significantly impact the RTD-based applications.

Selection of an appropriate tracer to measure the residence time distribution (RTD) of continuous powder blending operations

Residence time distributions (RTDs) are quickly becoming an important component of the quality control strategy for continuous manufacturing (CM) of pharmaceutical products. However, methodologies for determining RTDs, including appropriate selection of tracers and proper processing of RTD data, have not been fully developed, and there is potential to improve current methods.This work aims to implement protocols for tracer selection and establish a methodology for the determination and quantitative comparison of RTD curves obtained by the pulse method. We used an extensive material property data library and multivariate analyses to select appropriate tracers for active pharmaceutical ingredient (API) of interest. Tracer performance was evaluated in two continuous blenders using pulse input experiments. The equivalence of RTDs obtained from the API and the tracer was examined for formulations with widely different blend flow properties.For the most suitable tracer candidate, material properties were determined for mixtures with different API concentrations to ensure that blend properties containing varying amounts of tracer along the RTD profile remained similar to those of the target formulation. It was observed that even small changes in the physical properties of the target formulation would result in a different tracer RTD. This observation emphasized the importance of preserving the physical properties of the blend when characterizing the dynamical behavior of a unit operation.Further, the RTD of the tracer and the API in the blender were characterized under three different base flow properties. The outcome of these experiments enabled a fair side-by-side comparison of RTDs obtained using pulses of either API or tracer for powders with a varying range of properties. In finding an appropriate tracer, RTD profiles were compared quantitively using different methods. Multivariate analysis of variance (MANOVA) was shown to be a suitable tool for RTD profile comparisons.

Numerical investigation of engulfment flow at low Reynolds numbers in a T-shaped microchannel

Microreactors play a major role in the intensification of industrial processes. The performance of microfluidic devices depends on the flow behavior and flow regimes present in such systems. In this work, single-phase flow behavior and associated flow regimes in a T-shaped microchannel are numerically analyzed using computational fluid dynamics (CFD). To predict the single-phase flow regimes, three dimensional transient CFD simulations are performed. The critical Reynolds number (Re) at which flow regime transition and onset of engulfment occur is identified (Recritical = 300). To achieve engulfment flow at lower Re, the inlet geometry of the microchannel is modified as a convergent (C)–divergent (D) section and its effect on engulfment flow is analyzed. When the C/D ratio is 9:1, the predicted pressure drop (Δp) is found to be minimum (Recritical = 75, Δp = 5.4 kPa). The understanding of the engulfment flow regime is exploited through residence time distribution (RTD). The predicted RTD profiles indicate strong recirculation among vortices. The mixing index is calculated to quantify RTD, and it is found to be minimum when the C/D ratio is 9:1. The mixing performance is further verified by introducing buoyant particles in Lagrangian manner using discrete phase modeling. The predicted dynamics are qualitatively and quantitatively analyzed through Poincaré maps and Shannon’s entropy for various convergent–divergent inlets to characterize mixing. Once again, the C/D ratio of 9:1 supports in enhancing mixing in the microchannel. Hence, the proposed micromixer based on geometric modifications at the inlet helps achieve the engulfment flow regime at low Re.

Effect of oscillation amplitude on the residence time distribution for the mesoscale oscillatory baffled reactor

<p>A recent development in oscillatory baffled reactor technology is down-scaling the reactor, so that it can be used for the applications such as small-scale continuous production of bioethanol. A mesoscale oscillatory baffled reactor (MOBR) with central baffle system was developed and fabricated at mesoscales (typically 5 mm diameter). This present work aims to analyse the mixing conditions inside the MOBR by evaluating the residence time distribution (RTD) against the dynamic parameters of net flow Reynolds number (<em>Re</em><em><sub>n</sub></em>) at 4.2, 8.4 and 12.6 corresponding to flow rates of 1.0, 2.0 and 3.0 ml/min respectively, oscillatory Reynolds number (<em>Re</em><em><sub>o</sub></em>) between 62 to 622, and Strouhal number (<em>Str</em>) between 0.1 to 1.59. The effect of oscillation frequency and amplitude on RTD performance were studied at frequency, amplitude, and velocity ratio ranging from 4 to 8 Hz, 1 to 4 mm and 1 to 118, respectively. Effect of oscillation frequency has resulted in the variance of the RTD increased as the oscillation frequency increased from 5 Hz to 8 Hz and peak at 6 Hz of 0.264. A further increase in the frequency above 5 Hz caused the RTD to slightly broaden and positively skewed. At frequency of 5 Hz, the RTD profiles were close to Gaussian form for all tested amplitude values from 1 mm to 4 mm. At low amplitudes, i.e. xo = 1 mm, the variance exhibited its minimum around 0.842 at <em>Re</em><em><sub>o</sub></em><em> </em>=156. An increase in <em>Re</em><em><sub>o</sub></em><em> </em>above 300 resulted in increased in the variance rapidly to 1.28, and later eliminated the plug flow behaviour and the reactor behaved similar to a single continuous stirred tank reactor.</p><p>Chemical Engineering Research Bulletin 19(2017) 111-117</p>

Relationship between residence time distribution and forces applied by paddles on powder attrition during the die filling process

Abstract The die filling process, which happens prior to the compaction step, affects directly the quality of the final product (tablets). As paddles pass through the powder bed inside the feed frame, shear is applied to particles. Therefore, it is important to establish a relationship between residence time distribution (RTD) and forces applied by the feed frame paddles on powder attrition and overlubrication during the die filling process. The pulse injection method was used to study the RTD. The discrete element method (DEM) was also used to measure the RTD of particles by size ranges and the mean residence time (MRT) inside the feed frame. The experimental and DEM simulation design of experiments included 2 paddle wheel speeds (24 and 72 rpm) and 2 die disk speeds (29 and 57 rpm). Experimental results show that higher paddle wheel speeds lead to lower mean residence time, narrower RTD profiles, and larger number of paddle passes. The simulations RTD profiles are similar to an ideal continuous stirred tank reactor (CSTR) profile with a sharp peak and a tail. Operating conditions, feed frame exit contributions, and outlet mass flow rate affect the MRT. The RTD analysis by particle size shows that particle size segregation occurs where the smaller particles are leaving the feed frame faster. The level of powder confinement inside the feed frames can have a significant effect on powder attrition. As particle size increases, the compressive and tangential force applied to it increases. The tangential force data show that the level of attrition is also affected by the paddle wheel speed. This study explains in detail different factors that can affect the residence time distribution and the force applied to particles that can ultimately cause particle breakage and powder overlubrication.

Evaluation of full-scale membrane bioreactor mixing performance and the effect of membrane configuration

The design and optimisation of MBR units require knowledge of the biokinetics, fouling potential and mixing. Although the mixing within an MBR system is of critical importance to the performance, MBRs are mainly designed on the basis of biokinetics and fouling potential of the treatment system while assuming the hydrodynamic characteristics. One method to characterise the mixing is the residence time distribution (RTD). In this work, tracer studies using lithium chloride were performed to acquire RTD profiles of two full-scale MBR systems with different membrane configurations (flat sheet and hollow fibre). Analysis of the RTD profiles indicated that that both MBRs, including their respective filtration tanks, are very close to completely mixed. The mixing energy per volume of permeate used by the hollow fibre membrane vessel was lower than that of flat sheet module MBR; both in terms of whole MBR energy usage and membrane blower only energy usage. Hence, it is possible to conclude that the flat sheet MBR, per square metre of membrane, in this case, requires more energy to achieve a similar degree of mixing.

Diagnosis of membrane bioreactor performance through residence time distribution measurements — a preliminary study

It is recognised that the performance of a membrane bioreactor (MBR) is dependent upon the flow profile and hydraulic conditions in the reactor, the literature is silent on this aspect of MBR design. Consequently, there is poor understanding of the hydraulic conditions that exist within MBR's. One method to characterise the hydraulic conditions is based on the concept of residence time distribution (RTD). Careful measurement of the RTD profile reveals information on the degree of mixing in the reactor and any effects that the configuration of the membrane may have on the hydraulic conditions. This work focuses on developing a RTD technique for the study of the hydrodynamics and relating it to MBR process performance. The technique would be used as a tool to determine the impact of membrane geometry, orientation and mixing efficiency on MBR performance. RTD profiles were generated using the conservative tracer, lithium chloride, for a bench scale MBR's operating at the UNESCO centre in Sydney Australia and a pilot plant MBR located at South Windsor Australia. Analysis of the RTD profiles from the lead and tail membrane positions in the reactor in the absence of aeration indicated that different performance could occur in the same reactor. Increasing the aeration rate from 3.8 to 8.1 L/min did not affect the RTD data significantly in a bench scale MBR. However, it would be an important factor associated with reactor mixing and energy in larger municipal installations. The ‘‘Tanks-in-Series’’ model was used to simulate the performance of a pilot plant MBR. However, it was found that experimental RTD profiles could not be reproduced with this simple model. Consequently, we conclude that a more fundamental approach, based on computational fluid dynamics is needed to model the hydraulic behaviour in MBR's.

Evaluation of membrane bioreactor performance via residence time distribution: effects of membrane configuration and mixing

Unlike conventional wastewater treatment systems that have a single effluent discharge point, membrane bioreactors (MBR) may have multiple extraction points resulting from the location of the membrane element in the reactor. This leads to multiple residence time distributions for an MBR system. One method to characterise the mixing is based on the concept of residence time distribution (RTD). A set of RTDs were generated using the conservative tracer, lithium chloride, for pilot plant MBRs with capacity up to 300 m3/day. Flat sheet and hollow fibre pilot plant MBR systems were operated in parallel on primary effluent collected at the Bedok Water Reclamation Plant in the republic of Singapore. Analysis of the RTD profiles indicated that membrane geometry did not impact on the kinetic conversion associated with nitrification because both MBRs were in well mixed conditions. However, the energy required to achieve perfect mixing with a hollow fibre module MBR, as defined by the velocity gradient, was lower than that with a flat sheet module MBR. The implication is that energy input associated with reactor mixing will depend on the configuration of the membrane. The difference in energy requirements between flat sheets and hollow fibres is such that careful consideration should be given to membrane selection in larger municipal installations.

Indepth diagnosis of a secondary clarifier by the application of radiotracer technique and numerical modeling

To make an indepth diagnosis of a full-scale rectangular secondary clarifier, an experimental and numerical study has been performed in a wastewater treatment facility. Calculation results by the numerical model with the adoption of the SIMPLE algorithm of Patankar are validated with radiotracer experiments. Emphasis is given to the prediction of residence time distribution (RTD) curves. The predicted RTD profiles are in good agreement with the experimental RTD curves at the upstream and center sections except for the withdrawal zone of the complex effluent weir structure. The simulation results predict successfully the well-known flow characteristics of each stage such as the waterfall phenomenon at the front of the clarifier, the bottom density current and the surface return flow in the settling zone, and the upward flow in the exit zone. The detailed effects of density current are thoroughly investigated in terms of high SS loading and temperature difference between influent and ambient fluid. The program developed in this study shows the high potential to assist in the design and determination of optimal operating conditions to improve effluent quality in a full-scale secondary clarifier.

A comparative study of residence time distribution and selectivity in a monolith CDC reactor and a trickle bed reactor

A comparative study of the performance of a trickle bed reactor (TBR) and a monolith cocurrent downflow contactor (CDC) reactor in terms of selectivity and residence time distribution was conducted for the hydrogenation of 2-butyne-1,4-diol (B). Selectivity ( S) towards 2-butene-1,4-diol was investigated with the solvent 2-propanol and a 30% (v/v) 2-propanol/water mixture (M) in batch recycle mode. Liquid residence time distribution (RTD) curves were obtained for both reactors. Although both reactors presented almost identical hydrodynamic behaviour, i.e. RTD, significant differences regarding selectivity towards the alkene were observed in both solvents. The use of 2-propanol gave lower selectivities in both reactors, but even then the monolith reactor was superior. In the monolith CDC, the liquid RTD curve was also obtained at different radial positions. RTD profiles across the monolith showed that from the centre to the column wall there is possibly an increased retention of material and despite this, overall selectivity does not appear to be considerably depressed by the backmixing that the above result implies in 2-propanol/water where the selectivity was found to be 100% towards the intermediate (C). Modelling of the monolith CDC reactor was also conducted to predict RTD. The models tested were tanks-in-series, piston exchange and piston dispersion exchange; from which, piston exchange model was found to best predict and fit the experimental data.