Impact of material properties and process variables on the residence time distribution in twin screw feeding equipment.

Screw feeders are integrated as dispensing units in most continuous manufacturing platforms. Hence, characterizing and modelling the residence time distribution (RTD) of materials in feeders is indispensable to understand the traceability of raw materials from the drum till tablet, enabling the separation of non-confirming material. The proposed methodology addressed this leap in knowledge by characterizing materials, performing RTD trials according to an experimental design, applying RTD models and establishing a partial least square (PLS) regression model that links the material properties and process variables with the RTD responses as outputs. Results showed that RTD in screw feeders can be represented by a combination of plug-flow and mixed-flow. Three variables were found to impact the residence time distribution in feeders: flow rate, hopper level and conditioned bulk density. Interestingly, the plug-flow fraction was not affected by variation in flow rate or material properties. Consequently, simple PLS models could be developed that use density and flow rate to predict RTD at a given hopper level. This approach is powerful for RTD prediction based on bulk density in the early phases of development when control strategies for clinical manufacturing need to be established and material availability is still limited.

Breakage and drying behaviour of granules in a continuous fluid bed dryer: Influence of process parameters and wet granule transfer.

Although twin screw granulation has already been widely studied in recent years, only few studies addressed the subsequent continuous drying which is required after wet granulation and still suffers from a lack of detailed understanding. The latter is important for optimisation and control and, hence, a cost-effective practical implementation. Therefore, the aim of the current study is to increase understanding of the drying kinetics and the breakage and attrition phenomena during fluid bed drying after continuous twin screw granulation. Experiments were performed on a continuous manufacturing line consisting of a twin-screw granulator, a six-segmented fluid bed dryer, a mill, a lubricant blender and a tablet press. Granulation parameters were fixed in order to only examine the effect of drying parameters (filling time, drying time, air flow, drying air temperature) on the size distribution and moisture content of granules (both of the entire granulate and of size fractions). The wet granules were transferred either gravimetrically or pneumatically from the granulator exit to the fluid bed dryer. After a certain drying time, the moisture content reached an equilibrium. This drying time was found to depend on the applied airflow, drying air temperature and filling time. The moisture content of the granules decreased with an increasing drying time, airflow and drying temperature. Although smaller granules dried faster, the multimodal particle size distribution of the granules did not compromise uniform drying of the granules when the target moisture content was achieved. Extensive breakage of granules was observed during drying. Especially wet granules were prone to breakage and attrition during pneumatic transport, either in the wet transfer line or in the dry transfer line. Breakage and attrition of granules during transport and drying should be anticipated early on during process and formulation development by performing integrated experiments on the granulator, dryer and mill.

Multivariate statistical process control of a continuous pharmaceutical twin-screw granulation and fluid bed drying process.

A multivariate statistical process control (MSPC) strategy was developed for the monitoring of the ConsiGma™-25 continuous tablet manufacturing line. Thirty-five logged variables encompassing three major units, being a twin screw high shear granulator, a fluid bed dryer and a product control unit, were used to monitor the process. The MSPC strategy was based on principal component analysis of data acquired under normal operating conditions using a series of four process runs. Runs with imposed disturbances in the dryer air flow and temperature, in the granulator barrel temperature, speed and liquid mass flow and in the powder dosing unit mass flow were utilized to evaluate the model's monitoring performance. The impact of the imposed deviations to the process continuity was also evaluated using Hotelling's T2 and Q residuals statistics control charts. The influence of the individual process variables was assessed by analyzing contribution plots at specific time points. Results show that the imposed disturbances were all detected in both control charts. Overall, the MSPC strategy was successfully developed and applied. Additionally, deviations not associated with the imposed changes were detected, mainly in the granulator barrel temperature control.

Quantification aspects of constant pressure (ultra) high pressure liquid chromatography using mass-sensitive detectors with a nebulizing interface.

The present contribution investigates the quantitation aspects of mass-sensitive detectors with nebulizing interface (ESI-MSD, ELSD, CAD) in the constant pressure gradient elution mode. In this operation mode, the pressure is controlled and maintained at a set value and the liquid flow rate will vary according to the inverse mobile phase viscosity. As the pressure is continuously kept at the allowable maximum during the entire gradient run, the average liquid flow rate is higher compared to that in the conventional constant flow rate operation mode, thus shortening the analysis time. The following three mass-sensitive detectors were investigated: mass spectrometry detector (MS), evaporative light scattering detector (ELSD) and charged aerosol detector (CAD) and a wide variety of samples (phenones, polyaromatic hydrocarbons, wine, cocoa butter) has been considered. It was found that the nebulizing efficiency of the LC-interfaces of the three detectors under consideration changes with the increasing liquid flow rate. For the MS, the increasing flow rate leads to a lower peak area whereas for the ELSD the peak area increases compared to the constant flow rate mode. The peak area obtained with a CAD is rather insensitive to the liquid flow rate. The reproducibility of the peak area remains similar in both modes, although variation in system permeability compromises the 'long-term' reproducibility. This problem can however be overcome by running a flow rate program with an optimized flow rate and composition profile obtained from the constant pressure mode. In this case, the quantification remains reproducibile, despite any occuring variations of the system permeability. Furthermore, the same fragmentation pattern (MS) has been found in the constant pressure mode compared to the customary constant flow rate mode.

Comparison of the quantitative performance of constant pressure versus constant flow rate gradient elution separations using concentration-sensitive detectors.

This contribution discusses the difference in chromatographic performance when switching from the customary employed constant flow rate gradient elution mode to the recently re-introduced constant pressure gradient elution mode. In this mode, the inlet pressure is maintained at a set value even when the mobile phase viscosity becomes lower than the maximum mobile phase viscosity encountered during the gradient program. This leads to a higher average flow rate compared to the constant flow rate mode and results in a shorter analysis time. When both modes carry out the same mobile phase gradient program in volumetric units, normally identical selectivities are obtained. However, small deviations in selectivity are found due to the differences in pressure and viscous heating effects. These selectivity differences are of the same type as those observed when switching from HPLC to UHPLC and are inevitable when speeding up the analysis by applying a higher pressure. It was also found that, when using concentration-sensitive detectors, the constant pressure elution mode leads to identical peak areas as the constant flow rate mode. Also the linearity is maintained. In addition, the repeatability of the peak area and retention time remains the same when switching between both elution modes.

Kinetic performance limits of constant pressure versus constant flow rate gradient elution separations. Part I: theory.

We report on a general theoretical assessment of the potential kinetic advantages of running LC gradient elution separations in the constant-pressure mode instead of in the customarily used constant-flow rate mode. Analytical calculations as well as numerical simulation results are presented. It is shown that, provided both modes are run with the same volume-based gradient program, the constant-pressure mode can potentially offer an identical separation selectivity (except from some small differences induced by the difference in pressure and viscous heating trajectory), but in a significantly shorter time. For a gradient running between 5 and 95% of organic modifier, the decrease in analysis time can be expected to be of the order of some 20% for both water-methanol and water-acetonitrile gradients, and only weakly depending on the value of V(G)/V0 (or equivalently t(G)/t0). Obviously, the gain will be smaller when the start and end composition lie closer to the viscosity maximum of the considered water-organic modifier system. The assumptions underlying the obtained results (no effects of pressure and temperature on the viscosity or retention coefficient) are critically reviewed, and can be inferred to only have a small effect on the general conclusions. It is also shown that, under the adopted assumptions, the kinetic plot theory also holds for operations where the flow rate varies with the time, as is the case for constant-pressure operation. Comparing both operation modes in a kinetic plot representing the maximal peak capacity versus time, it is theoretically predicted here that both modes can be expected to perform equally well in the fully C-term dominated regime (where H varies linearly with the flow rate), while the constant pressure mode is advantageous for all lower flow rates. Near the optimal flow rate, and for linear gradients running from 5 to 95% organic modifier, time gains of the order of some 20% can be expected (or 25-30% when accounting for the fact that the constant pressure mode can be run without having to leave a pressure safety margin of 5-10% as is needed in the constant flow rate mode).

Kinetic performance limits of constant pressure versus constant flow rate gradient elution separations. Part II: experimental.

We report on a first series of experiments comparing the selectivity and the kinetic performance of constant flow rate and constant pressure mode gradient elution separations. Both water-methanol and water-acetonitrile mobile phase mixtures have been considered, as well as different samples and gradient programs. Instrument pressures up to 1200 bar have been used. Neglecting some small possible deviations caused by viscous heating effects, the experiments could confirm the theoretical expectation that both operation modes should lead to identical separation selectivities provided the same mobile phase gradient program is run in reduced volumetric coordinates. Also in agreement with the theoretical expectations, the cP-mode led to a gain in analysis time amounting up to some 17% for linear gradients running from 5 to 95% of organic modifier at ultra-high pressures. Gains of over 25% were obtained for segmented gradients, at least when the flat portions of the gradient program were situated in regions where the gradient composition was the least viscous. Detailed plate height measurements showed that the single difference between the constant flow rate and the constant pressure mode is a (small) difference in efficiency caused by the difference in average flow rate, in turn leading to a different intrinsic band broadening. Separating a phenone sample with a 20-95% water-acetonitrile gradient, the cP-mode leads to gradient plate heights that are some 20-40% smaller than in the cF-mode in the B-term dominated regime, while they are some 5-10% larger in the C-term dominated regime. Considering a separation with sub 2-µm particles on a 350 mm long coupled column, switching to the constant pressure mode allowed to finish the run in 29 instead of in 35 min, while also a larger peak capacity is obtained (going from 334 in the cF-mode to 339 in the cP-mode) and the mutual selectivity between the different peaks is fully retained.

Towards a solution for viscous heating in ultra-high pressure liquid chromatography using intermediate cooling.

A generic solution is proposed for the deleterious viscous heating effects in adiabatic or near-adiabatic systems that can be expected when trying to push the column operating pressures above the currently available range of ultra-high pressures (i.e., 1200 bar). A set of proof-of-principle experiments, mainly using existing commercial equipment, is presented. The solution is based on splitting up a column with given length L into n segments with length L/n, and providing an active cooling to the capillaries connecting the segments. In this way, the viscous heat is removed at a location where the radial heat removal does not lead to an efficiency loss (i.e., in the thin connection capillaries), while the column segments can be operated under near-adiabatic conditions without suffering from an unacceptable rise of the mobile phase temperature. Experimental results indicate that the column segmentation does not lead to a significant efficiency loss (comparing the performance of a 10 cm column with a 2 cm x 5 cm column system), whereas, as expected, the system displays a much improved temperature stability, both in time (because of the shortened temperature transient times) and in space (reduction of the average axial temperature rise by a factor n). The method also prevents a large backflow of heat along the column wall that would lead to large efficiency losses if one would attempt to operate columns at pressures of 1500 bar or more. A real-world pharmaceutical example is given where this improved temperature robustness could help in moderating the changes in selectivity during method transfer from a low to a high pressure operation, although the complex non-linear behavior of the viscous heating and high pressure effects result in lower than expected improvement.