The Challenge of Die Filling in Rotary Presses: A Systematic Study of Material Properties and Process Parameters

For the efficient and safe production of pharmaceutical tablets, a deep process understanding is of high importance. An essential process step during tableting is the die filling, as it is responsible for a consistent tablet weight and drug content. Furthermore, it affects the results of subsequent process steps, compaction and ejection, and thus critical quality attributes. This study focuses on understanding the influences of process parameters and material properties on die filling on a rotary tablet press. By the systematic variation in process parameters as the turret and paddle speeds as well as the fill and dosing depths, five formulations with differing properties are processed. Analysis of the normalized tablet weight, called filling yield, revealed different limitation mechanisms of the filling process, i.e., incomplete filled dies for certain parameter settings. Kinetic limitations occur due to a short residence time under the feed frame (filling time) caused by high turret speeds, which additionally induce high tablet weight variation coefficients. Characteristic maximum turret speeds at certain paddle speeds can be found to still achieve complete filling. At low turret speeds, densification of the powder inside the dies takes place, induced by two mechanisms: either high paddle speeds or high overfill ratios, or a combination of both. The challenge to fill the dies completely as well as avoid densification is dependent on material properties as the flowability. The mass discharge rate from an orifice was found to be in a linear correlation to the filling results of different formulations below complete filling

Impact of Particle and Equipment Properties on Residence Time Distribution of Pharmaceutical Excipients in Rotary Tablet Presses

Paddle feeders are devices commonly used in rotary tablet presses to facilitate constant and efficient die filling. Adversely, the shear stress applied by the rotating paddles is known to affect the bulk properties of the processed powder dependent on the residence time. This study focuses on the residence time distribution (RTD) of two commonly applied excipients (microcrystalline cellulose, MCC; dicalcium phosphate, DCP), which exhibit different flow properties inside rotary tablet presses. To realistically depict the powder flow inside rotary tablet presses, custom-made tracer powder was developed. The applied method was proven to be appropriate as the tracer and bulk powder showed comparable properties. The RTDs of both materials were examined in two differently scaled rotary tablet presses and the influence of process parameters was determined. To analyze RTDs independent of the mass flow, the normalized variance was used to quantify intermixing. Substantial differences between both materials and tablet presses were found. Broader RTDs were measured for the poorer flowing MCC as well as for the production scale press. The obtained results can be used to improve the general understanding of powder flow inside rotary tablet presses and amplify scale-up and continuous production process development

Scaling Tableting Processes from Compaction Simulator to Rotary Presses - Mind the Sub-Processes

Compaction simulators are frequently used in the formulation and process development of tablets, bringing about the advantages of flexibility, low material consumption, and high instrumentation to generate the most possible process understanding. However, their capability of resembling general aspects of rotary press compaction and their precision in simulating or mimicking sub-processes such as feeding and filling need to be systematically studied. The effect of material deformation behavior, blend composition, and feeding on tensile strength and simulation precision as compared with rotary presses of different scales is evaluated in this study. Generally, good simulation performance was found for the studied compaction simulator. Compaction profile-sensitivity was demonstrated for highly visco-plastic materials while shear-sensitivity in feeding was demonstrated for lubricated blends of ductile particles. Strategies for the compensation of both in compaction simulator experiments are presented by careful investigation of the compaction stress over time profiles and introduction of a compaction simulator-adapted shear number approach to account for differences in layout and operation mode between compaction simulator and rotary press, respectively. These approaches support the general aim of this study to provide a more straightforward determination of scaling process parameters between rotary press and compaction simulator and facilitate a quicker and more reliable process transfer

Influence of High, Disperse API Load on Properties along the Fused-Layer Modeling Process Chain of Solid Dosage Forms

In order to cope with the increasing number of multimorbid patients due to demographic changes, individualized polypill solutions must be developed. One promising tool is fused layer modeling (FLM) of dosage forms with patient-specific dose combinations and release individualization. As there are few approaches reported that systematically investigate the influence of high disperse active pharmaceutical ingredient (API) loads in filaments needed for FLM, this was the focus for the present study. Different filaments based on polyethylene oxide and hypromellose (HPMC) with different loads of theophylline as model API (up to 50 wt.%) were extruded with a twin-screw extruder and printed to dosage forms. Along the process chain, the following parameters were investigated: particle size and shape of theophylline; mechanical properties, microstructure, mass and content uniformity of filaments as well as dosage forms and the theophylline release from selected dosage forms. Especially for HPMC, increasing theophylline load enhanced the flexural strength of filaments whilst the FLM accuracy decreased inducing defects in microstructure. Theophylline load had no significant effect on the dissolution profile of HPMC-based dosage forms. Therefore, a thorough analysis of particle-induced effects is necessary to correlate mechanical properties of filaments, printability, and the dosage-and-release profile adjustment

Characterisation of Water Uptake and swelling Force of pharmaceutical Tablets

Tablets are the most common dosage form in the pharmaceutical industry. Rapid drug release is ensured by quick tablet disintegration which is caused by the absorption of water into the tablet. Therefore, water uptake and subsequent volume expansion are necessary requirements for tablet disintegration. In this work, binary mixtures of excipients were compacted to tablets with varying structural and mechanical properties to determine the influence of formulation and process parameters on water uptake and resulting swelling force of tablets. Results showed strong influences of disintegrant concentration as well as tablet porosity on both absorbed amount of water and acting swelling force. Obtained results revealed that water uptake and swelling force measurements are useful tools for an improved understanding of tablet disintegration

Investigation of Nanoporous Superalloy Membranes for the Production of Nanoemulsions

Premix membrane emulsification is a gentle process for producing nanoemulsions, i.e., for pharmaceutical purposes. The operating time of common membranes is short today, because of their fragility, membrane fouling and poor cleanability. In contrast, superalloy membranes are cleansable because of their high mechanical strength as well as high chemical and thermal resistances and therefore, could achieve clearly longer operating times. Their usability for premix membrane emulsification is investigated in this study. Different flow rates of the premix emulsion were tested up to 21 cycles with a small-scale extruder, three different nanoporous superalloy membrane structures have been tested in comparison to a common polymer membrane. Varying the two-phase-structure ( - and 0-phase) of superalloy bulk material through thermal or thermo-mechanical treatments and chemical extraction of either one of the phases, different membrane microstructures could be obtained. These membranes differ in pore size, pore structure, and porosity, resulting in different flow resistances, droplet sizes and droplet size distributions in the investigated premix membrane emulsification process. Emulsions with droplet sizes in the desired range of 100 to 500 nm and with acceptable droplet size distributions were achieved. Data display an improved process stability for superalloy membranes, however, special attention needs to be paid towards narrow droplet size distributions

Characterization of Mechanical Property Distributions on Tablet Surfaces

Powder densification through uniaxial compaction is governed by a number of simultaneous processes taking place on a reduced time as the result of the stress gradients within the packing, as well as the frictional and adhesive forces between the powder and the die walls. As a result of that, a density and stiffness anisotropy is developed across the axial and radial directions. In this study, microindentation has been applied to assess and quantify the variation of the module of elasticity (Emod) throughout the surface of cylindrical tablets. A representative set of deformation behaviors was analyzed by pharmaceutical excipients ranging from soft/plastic behavior (microcrystalline cellulose) over medium (lactose) to hard/brittle behavior (calcium phosphate) for different compaction pressures. The results of the local stiffness distribution over tablet faces depicted a linear and directly proportional tendency between a solid fraction and Emod for the upper and lower faces, as well as remarkable stiffness anisotropy between the axial and radial directions of compaction. The highest extent of the stiffness anisotropy that was found for ductile grades of microcrystalline cellulose (MCC) in comparison with brittle powders has been attributed to the dual phenomena of overall elastic recovery and Poisson’s effect on the relaxation kinetics. As a reinforcement of this analysis, the evolution of the specific surface area elucidated the respective densification mechanism and its implementations toward anisotropy. For ductile excipients, the increase in the contact surface area as well as the reduction and closing of interstitial pores explain the reduction of surface area with increasing compaction pressure. For brittle powders, densification evolves through fragmentation and the subsequent filling of voids

A Mathematical Approach to Consider Solid Compressibility in the Compression of Pharmaceutical Powders.

In-die compression analysis is an effective method for the characterization of powder compressibility. However, physically unreasonable apparent solid fractions above one or apparent in-die porosities below zero are often calculated for higher compression stresses. One important reason for this is the neglect of solid compressibility and hence the assumption of a constant solid density. In this work, the solid compressibility of four pharmaceutical powders with different deformation behaviour is characterized using mercury porosimetry. The derived bulk moduli are applied for the calculation of in-die porosities. The change of in-die porosity due to the consideration of solid compressibility is for instance up to 4% for microcrystalline cellulose at a compression stress of 400 MPa and thus cannot be neglected for the calculation of in-die porosities. However, solid compressibility and further uncertainties from, for example the measured solid density and from the displacement sensors, are difficult or only partially accessible. Therefore, a mathematic term for the calculation of physically reasonable in-die porosities is introduced. This term can be used for the extension of common mathematical models, such as the models of Heckel and of Cooper & Eaton. Additionally, an extended in-die compression function is introduced to precisely describe the entire range of in-die porosity curves and to enable the successful differentiation and quantification of the compression behaviour of the investigated pharmaceutical powders