Valérie Vanhoorne

Conceptual framework for model-based analysis of residence time distribution in twin-screw granulation

Twin-screw granulation is a promising continuous alternative for traditional batchwise wet granulation processes. The twin-screw granulator (TSG) screws consist of transport and kneading element modules. Therefore, the granulation to a large extent is governed by the residence time distribution within each module where different granulation rate processes dominate over others. Currently, experimental data is used to determine the residence time distributions. In this study, a conceptual model based on classical chemical engineering methods is proposed to better understand and simulate the residence time distribution in a TSG. The experimental data were compared with the proposed most suitable conceptual model to estimate the parameters of the model and to analyse and predict the effects of changes in number of kneading discs and their stagger angle, screw speed and powder feed rate on residence time. The study established that the kneading block in the screw configuration acts as a plug-flow zone inside the granulator. Furthermore, it was found that a balance between the throughput force and conveying rate is required to obtain a good axial mixing inside the twin-screw granulator. Although the granulation behaviour is different for other excipients, the experimental data collection and modelling methods applied in this study are generic and can be adapted to other excipients.

Development of a controlled release formulation by continuous twin screw granulation: Influence of process and formulation parameters.

The aim of this study was to evaluate the potential of twin screw granulation for the continuous production of controlled release formulations with hydroxypropylmethylcellulose as hydrophilic matrix former. Metoprolol tartrate was included in the formulation as very water soluble model drug. A premix of metoprolol tartrate, hydroxypropylmethylcellulose and filler (ratio 20/20/60, w/w) was granulated with demineralized water via twin screw granulation. After oven drying and milling, tablets were produced on a rotary Modul™ P tablet press. A D-optimal design (29 experiments) was used to assess the influence of process (screw speed, throughput, barrel temperature and screw design) and formulation parameters (starch content of the filler) on the process (torque), granule (size distribution, shape, friability, density) and tablet (hardness, friability and dissolution) critical quality attributes. The torque was dominated by the number of kneading elements and throughput, whereas screw speed and filling degree only showed a minor influence on torque. Addition of screw mixing elements after a block of kneading elements improved the yield of the process before milling as it resulted in less oversized granules and also after milling as less fines were present. Temperature was also an important parameter to optimize as a higher temperature yielded less fines and positively influenced the aspect ratio. The shape of hydroxypropylmethylcellulose granules was comparable to that of immediate release formulations. Tensile strength and friability of tablets were not dependent on the process parameters. The use of starch as filler was not beneficial with regard to granule and tablet properties. Complete drug release was obtained after 16-20h and was independent of the designs parameters.

Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation

In most formulations processed via continuous twin screw granulation microcrystalline cellulose (MCC) and/or lactose are used as excipients, but mannitol is also a preferred excipient for wet granulation and tableting due to its non-hygroscopicity and inertness. Therefore, the aim of the current study was to investigate the influence of process parameters on critical quality attributes of granules (moisture content, solid state, morphology, size distribution, specific surface area, friability, flowability and hygroscopicity) and tablets (tensile strength and friability) after twin screw granulation of δ-mannitol. The δ-polymorph was selected since a moisture-induced transformation to β-mannitol was observed during batch wet granulation, which exhibited a unique morphology with a large surface area and improved tabletability. A full factorial experimental design was performed, varying screw speed (400-900rpm), granulation temperature (25-40°C), number of kneading elements (6 or 12) and liquid-to-solid (L/S) ratio, on the granulation unit of a ConsiGma™-25 line (a continuous powder-to-tablet manufacturing system). After tray drying the granules were milled and tableted. The results showed that the polymorphic transition from δ- to β-mannitol also occurred during twin screw granulation, although the residence time and L/S ratios were much lower in continuous twin screw granulation compared to batch processing. However, the polymorphic transition was not complete in all experiments and depended on the L/S ratio, screw speed and number of kneading elements. Nevertheless all granules exhibited the unique morphology linked to the polymorphic transition and had a superior tabletability compared to granules produced with β-mannitol as starting material. This was attributed to enhanced plastic deformation of the granules manufactured using δ-mannitol as starting material. In addition, it was concluded that mannitol was granulated via a different mechanism than other, less-soluble, excipients (e.g. lactose, microcrystalline cellulose) due to its high solubility and dissolution rate as the influence of process parameters on the mannitol granule characteristics was different.

Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation

Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid-liquid mixing must be achieved quickly by appropriate arrangement of transport and kneading elements in the granulator screw allowing the production of granules with a size distribution appropriate for tableting. The distribution of residence time and granulation liquid is governed by the field conditions (such as location and length of mixing zones) in the twin-screw granulator, thus contain interesting information on granulation time, mixing and resulting sub-processes such as wetting, aggregation and breakage. In this study, the impact of process (feed rate, screw speed and liquid-to-solid ratio) and equipment parameters (number of kneading discs and stagger angle) on the residence time (distribution), the granulation liquid-powder mixing and the resulting granule size distributions during twin-screw granulation were investigated. Residence time and axial mixing data was extracted from tracer maps and the solid-liquid mixing was quantified from moisture maps, obtained by monitoring the granules at the granulator outlet using near infra-red chemical imaging (NIR-CI). The granule size distribution was measured using the sieving method. An increasing screw speed dominantly reduced the mean residence time. Interaction of material throughput with the screw speed and with the number of kneading discs led to most variation in the studied responses including residence time and mixing capacity. At a high screw speed, granulation yield improved due to high axial mixing. However, increasing material throughput quickly lowers the yield due to insufficient mixing of liquid and powder. Moreover, increasing liquid-to-solid ratio resulted in more oversized granules, and the fraction of oversized granules further increased at higher throughput. Although an increasing number of kneading discs was found to be critical for achieving a uniform distribution of the granulation liquid, the granulation performance was hampered due to insufficient solid-liquid mixing capacity of the current kneading discs which is essential for wet granulation. Thus, a balance between material throughput and screw speed should be strived for in order to achieve a specific granulation time and solid-liquid mixing for high granulation yield. Additionally, more efforts are needed both in modification of the screw configuration as well as the geometry of the mixing elements to improve the mixing capacity of the twin-screw granulator. The results from the current experimental study improved the understanding regarding the interplay between granulation time and the axial and solid-liquid mixing responsible for the granulation performance in twin-screw wet granulation.

Development of a continuous direct compression platform for low-dose drug products

In this work a continuous direct compression process was developed for a low-dosed drug product. Each unit operation of the GEA CDC-50 system was thoroughly investigated. This paper aimed to tackle the macroscopic and microscopic blend uniformity challenges inherently associated with continuous direct compression of cohesive and agglomerated APIs formulated at low dose. Density, compressibility and flow were identified as key material properties at the feeding stage. The screw speed coupled with powder flow regulated the gravimetric feeding performance. The impact of process and design variables was elucidated at the blending stage. The impeller configuration (number and pattern of radial mixing blades) and speed were key variables to steer the residence time distribution at the blending stage. An impeller configuration with distributed radial mixing blades could sufficiently filter the steady state feeding variability at low mixer speed, but exerted limited strain and shear on the blend. Hence micro-agglomerates persisted through the blending process and occasionally resulted in super potent tablets. Therefore, a new configuration was evaluated with more radial mixing blades centered on the impeller. This configuration resulted in a long mixing time at high tip speed which induced a maximized strain and shear. Consequently, excellent uniformity of the blend and tablets at macroscopic and microscopic level was achieved. Besides, this impeller improved robustness towards feeding disturbances, changes in process settings and variable blend properties. Next, it was demonstrated that the lubrication step requires critical attention during the design of the equipment, formulation and process. This study provided abundant evidence that an optimized continuous direct compression process allows direct compression of challenging low-dose drug products.

Continuous manufacturing of delta mannitol by cospray drying with PVP.

Mannitol is a frequently used diluent in the production of tablets due to its non-hygroscopic character and low drug interaction potential. Although the δ-polymorph of mannitol has superior tabletability in comparison to α- and β-mannitol, the latter are most commonly used because large-scale production of δ-mannitol is difficult. Therefore, a continuous method for production of δ-mannitol was developed in the current study. Spray drying an aqueous solution of mannitol and PVP in a ratio of 4:1 resulted in formation of δ-mannitol. The tabletability of a physical mixture of spray dried δ-mannitol with PVP (5%) and paracetamol (75%) was clearly superior to the tabletability of physical mixtures consisting of spray dried α- and β-mannitol with PVP (5%) and paracetamol (75%) which confirmed the excellent tableting properties of the δ-polymorph. In addition, a coprocessing method was applied to coat paracetamol crystals with δ-mannitol and PVP. The tabletability of the resulting coprocessed particles consisting of 5% PVP, 20% δ-mannitol and 75% paracetamol reached a maximal tensile strength of 2.1 MPa at a main compression pressure of 260 MPa. Moreover the friability of tablets compressed at 184 MPa was only 0.5%. This was attributed to the excellent compression properties of δ-mannitol and the coating of paracetamol crystals with δ-mannitol and PVP during coprocessing.

3D printing of high drug loaded dosage forms using thermoplastic polyurethanes

It was the aim of this study to develop high drug loaded (>30%, w/w), thermoplastic polyurethane (TPU)-based dosage forms via fused deposition modelling (FDM). Model drugs with different particle size and aqueous solubility were pre-processed in combination with diverse TPU grades via hot melt extrusion (HME) into filaments with a diameter of 1.75 ± 0.05 mm. Subsequently, TPU-based filaments which featured acceptable quality attributes (i.e. consistent filament diameter, smooth surface morphology and good mechanical properties) were printed into tablets. The sustained release potential of the 3D printed dosage forms was tested in vitro. Moreover, the impact of printing parameters on the in vitro drug release was investigated. TPU-based filaments could be loaded with 60% (w/w) fine drug powder without observing severe shark skinning or inconsistent filament diameter. During 3D printing experiments, HME filaments based on hard TPU grades were successfully converted into personalized dosage forms containing a high concentration of crystalline drug (up to 60%, w/w). In vitro release kinetics were mainly affected by the matrix composition and tablet infill degree. Therefore, this study clearly demonstrated that TPU-based FDM feedstock material offers a lot of formulation freedom for the development of personalized dosage forms.

Continuous twin screw granulation of controlled release formulations with various HPMC grades

HPMC is a popular matrix former to formulate tablets with extended drug release. Tablets with HPMC are preferentially produced by direct compression. However, granulation is often required prior to tableting to overcome poor flowability of the formulation. While continuous twin screw granulation has been extensively evaluated for granulation of immediate release formulations, twin screw granulation of controlled release formulations including the dissolution behavior of the formulations received little attention. Therefore, the influence of the HPMC grade (viscosity and substitution degree) and the particle size of theophylline on critical quality attributes of granules (continuously produced via twin screw granulation) and tablets was investigated in the current study. Formulations with 20 or 40% HPMC, 20% theophylline and lactose were granulated with water at fixed process parameters via twin screw granulation. The torque was influenced by the viscosity and substitution degree of HPMC, but was not a limiting factor for the granulation process. An optimal L/S ratio was selected for each formulation based on the granule size distribution. The granule size distributions were influenced by the substitution degree and concentration of HPMC and the particle size of theophylline. Raman and UV spectroscopic analysis on 8 sieve fractions of granules indicated an inhomogeneous distribution of theophylline over the size fractions. However, this phenomenon was not correlated with the hydration rate or viscosity of HPMC. Controlled release of theophylline could be obtained over 24h with release profiles close to zero-order. The release of theophylline could be tailored via selection of the substitution degree and viscosity of HPMC.

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 models monitoring performance. The impact of the imposed deviations to the process continuity was also evaluated using Hotellings 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.

Lubricant sensitivity in function of paddle movement in the forced feeder of a high-speed tablet press

Abstract Context: The negative impact of magnesium stearate (MgSt) on the hardness of tablets is a well-known phenomenon, but the influence of paddle movement in the forced feeder on the lubricant effect during tablet compression is often neglected. Objective: The purpose of this research was to investigate the influence of paddle speed in the forced feeder on tablet tensile strength (TS). Materials and methods: Mixtures of microcrystalline cellulose (MCC) and MgSt (0.5%) were blended using different methods (low & high shear). After blending, the formulations were compressed into tablets. All parameters of the tableting cycle were kept constant except the speed of the paddles in the forced feeder. Results and discussion: The blending technique affected the sensitivity of the formulation to the paddle speed. The TS of pure MCC tablets did not change in function of paddle speed, while tablets prepared by low shear mixing became softer at higher paddle speed. The TS of tablets manufactured using the high-shear mixed blend was low and did not vary in function of paddle speed, suggesting that overlubrication already occurred during the initial blending step. Furthermore, analysis of the machine parameters allowed evaluation of the influence of the paddles on the flowability, initial packing, and compactability of the powder mixtures. Conclusion: The results elucidated that during manufacturing of tablets using MgSt-containing blends care should not only be taken during the blending step prior to tableting, but also during the tableting process itself, as paddle speed can affect tablet TS, a critical quality attribute.