Batch vs. continuous direct compression - a comparison of material processability and final tablet quality.

In this study, an in-depth comparison was made between batch and continuous direct compression using similar compression set-ups. The overall material processability and final tablet quality were compared and evaluated. Correlations between material properties, process parameters and final tablet properties were made via multivariate data analyses. In total, 10 low-dosed (1% w/w) and 10 high-dosed (40% w/w) formulations were processed, using a total of 10 different fillers/filler combinations. The trials indicated that the impact of filler type, drug load or process settings was similar for batch and continuous direct compression. The main differentiator between batch and continuous was the flow dynamics in the operating system, where properties related to flow, compressibility and permeability played a crucial role. The less consistent flow throughout a batch process resulted in a significantly higher variability within the tablet press (σCF) and for the tablet quality responses (σMass, σTS). However, the better controlled blending procedure prior to batch processing was reflected in a more consistent API concentration variability. Overall, the comparison showed the benefits of selecting appropriate excipients and process settings to achieve a specific outcome, keeping in mind some key differentiators between both processes.

Semi-crystalline materials for pharmaceutical fused filament fabrication: Dissolution and porosity.

A better understanding of crystallization kinetics and the effect on drug product quality characteristics is needed to exploit the use of semi-crystalline polymers in pharmaceutical fused filament fabrication. Filaments were prepared from polycaprolactone or polyethylene oxide loaded with a crystallization inhibitor or inducer, which was either 10% (w/w) ibuprofen or theophylline. A design-of-experiments approach was conducted to investigate the effect of nozzle temperature, bed temperature and print speed on the printed tablets' microstructure and dissolution kinetics. Helium pycnometry derived porosity proved an ideal technique to capture significant distortions in the tablets' microstructure. On the other hand, terahertz time domain spectroscopy (THz-TDS) analysis proved valuable to investigate additional enclosed pores of the tablets' microstructure. The surface roughness was analyzed using optical coherence tomography, showing the importance of extensional viscosity for printed drug products. Drug release occurred via erosion for tablets consisting of polyethylene oxide, which partly reduced the effect of the inner microstructure on the drug release kinetics. An initial burst release effect was noted for polycaprolactone tablets, after which drug release continued via diffusion. Both the pore and crystalline microstructure were deemed essential to steer drug release. In conclusion, this research provided guidelines for material and process choice when a specific microstructure has to be constructed from semi-crystalline materials. In addition, non-destructive tests for the characterization of printed products were evaluated.

Visualization of the granule temperature using thermal imaging to improve understanding of the granulation mechanism in continuous twin-screw melt granulation.

The aim of this study is to increase process understanding of the granulation mechanism in twin-screw melt granulation by evaluating the influence of different screw configurations on granule formation and granule temperature via thermal imaging. The study used a Design of Experiments (DoE) to process a miscible and immiscible formulation (85% API/binder w/w) using a twin-screw extruder with varying screw configurations. The barrel temperature (°C), screw speed (rpm), throughput (kg/h), and kneading zone (direction and stagger angle) were varied. Granule and process properties were evaluated for samples collected at four different locations along the length of the granulation barrel to visualize the granule formation, and granule temperature was monitored by an infrared camera to measure heat transfer on the granules. The resulting temperature was linked to the granule properties and the granule formation along the length of the barrel. The most influencing factors on the granule temperature are the direction of the kneading zone and the set barrel temperature. It was observed that granule formation mainly occurred in the zones that apply more kneading on the granules. The highest temperature increase was observed when the smallest stagger angle in reverse configuration was used, and could be linked to better granule quality attributes.

Drying behaviour and visualization of surfactants after co-spray drying of surfactant-stabilized aqueous suspensions.

Surfactants are widely used in many industries as dispersants or flocculants for suspensions. As the addition of low concentrations of surfactant is sufficient to execute their effect, they barely alter the formulation composition. In this research it was examined whether surfactants, in particular polysorbate 80 (PS80), were suitable as suspension stabilizers for co-spray drying of drug-filler combinations. Therefore, their drying behaviour at different process and formulation settings was studied and mapped by means of fluorescently labelled PS80. Co-spray drying of 10% w/w aqueous suspensions stabilized with 0.1% w/w PS80 resulted in excessive loss of sticky powder in the conical lower part of the drying chamber and the powder conveyor ducts. Up to 16% of powder was lost in the first transporter (i.e. the first part of the conveyor ducts). The amount of powder deposited in the first transporter, and by extension the stickiness of the recovered powder, was correlated with the presence of PS80 on the surface of the spray dried particles. Redistribution of free surfactant molecules during droplet drying depended on the process and formulation parameters. Enrichment of PS80 at the particle surface was most pronounced after co-spray drying of liquid feedstocks with low suspended fraction at process conditions favouring rapid droplet drying.

Exploiting common ion addition to accelerate zolpidem hemitartrate release from Eudragit EPO extrudates.

The current study aimed at optimizing a previously developed non-clinical formulation for use in zolpidem deprescribing. The formulation under investigation consists of extruded zolpidem hemitartrate (30% w/w) and Eudragit EPO (70% w/w) mixtures which display unsatisfactory dissolution behavior. Both milled extrudates and physical mixtures were compressed to produce tablets with identical target weight and solid fraction. First, the susceptibility of zolpidem hemitartrate towards heat and shear degradation was identified utilizing thermal and HPLC-DAD analysis. The drug salt proved prone to thermally induced disproportionation. Moreover, the impurity content increased after applying hot melt extrusion although ICH guidelines were still attained. Secondly, extrudates and physical mixtures were subjected to FTIR analysis. As a result, interaction and protonation of the dimethyl aminoethyl group from Eudragit EPO resulting from zolpidem disproportionation was elucidated. As such, the formulations' slow dissolution kinetics in comparison to formulations containing non-ionizable polymers (e.g. Kollidon 12PF and Kollidon VA64) is explained. Finally, addition of tartaric acid, a microenvironmental pH modulator and common ion, proved a successful method to increase dissolution kinetics. The amount of drug released after 15 min increased drastically from 10 to 40% upon the addition of 5% tartaric acid. Immediate release behavior (80% within 15 min) was however not yet attained.

Elucidation of granulation mechanisms along the length of the barrel in continuous twin-screw melt granulation.

In the pharmaceutical industry, innovative continuous manufacturing technologies such as twin-screw melt granulation (TSMG) are gaining more and more interest to process challenging formulations. To enable the implementation of TSMG, more elucidation of the process is required and this study provides a better understanding of the granule formation along the length of the barrel. By sampling at four different zones, the influence of screw configuration, process parameters and formulation is investigated for the granule properties next to the residence time distribution. It showed that conveying elements initiate the granulation by providing a limited heat transfer into the powder bed. In the kneading zones, the consolidation stage takes place, shear elongation combined with breakage and layering is occurring for the reversed configurations and densification with breakage and layering for the forward and neutral configurations. Due to the material build-up in the reversed configurations, these granules are larger, stronger, more elongated and less porous due to the higher degree of shear and densification. This configuration also shows a significantly longer residence time compared to the forward configuration. Hence, the higher level of shear and the longer period of time enables more melting of the binder resulting in successful granulation.

Identification of continuous twin-screw melt granulation mechanisms for different screw configurations, process settings and formulation.

Twin-screw melt granulation (TSMG) is a promising continuous manufacturing technology for the processing of high drug load formulations and to formulate heat- and moisture-sensitive active pharmaceutical ingredients (APIs). This study evaluates the influence of process parameters for TSMG, mainly focusing on the effect of the screw configuration combined with screw speed, throughput and barrel temperature, to elucidate the melt granulation mechanisms. For the kneading zone, the stagger angle was varied between 30°, 60° and 90°, and investigated for both the forward and the reversed direction. In addition to the process parameters, the influence of the formulation differing in their API-binder miscibility was evaluated. As responses, the granule (size, friability and porosity) and process properties such as torque were evaluated, indicating that the screw configuration is the most influential factor. Nucleation, consolidation and breakage are the granulation mechanisms for the forward and the neutral configuration, while consolidation and densification with shear elongation are identified for the reversed configuration. The formulations differ mainly in the forward and neutral configuration since the immiscible formulation shows a bimodal granule size distribution with a larger fraction of fines and weaker granules is obtained. For the reversed configuration, similar granulation mechanisms are seen for both formulations.

Continuous direct compression: Development of an empirical predictive model and challenges regarding PAT implementation.

In this study, an empirical predictive model was developed based on the quantitative relationships between blend properties, critical quality attributes (CQA) and critical process parameters (CPP) related to blending and tableting. The blend uniformity and API concentration in the tablets were used to elucidate challenges related to the processability as well as the implementation of PAT tools. Thirty divergent ternary blends were evaluated on a continuous direct compression line (ConsiGma™ CDC-50). The trials showed a significant impact of the impeller configuration and impeller speed on the blending performance, whereas a limited impact of blend properties was observed. In contrast, blend properties played a significant role during compression, where changes in blend composition significantly altered the tablet quality. The observed correlations allowed to develop an empirical predictive model for the selection of process configurations based on the blend properties, reducing the number of trial runs needed to optimize a process and thus reducing development time and costs of new drug products. Furthermore, the trials elucidated several challenges related to blend properties that had a significant impact on PAT implementation and performance of the CDC-platform, highlighting the importance of further process development and optimization in order to solve the remaining challenges.

In-depth analysis of the long-term processability of materials during continuous feeding.

This study determined the feasibility of long-term continuous powder feeding and its effect on the overall process performance. Additionally, quantitative relationships were established between material properties, process settings and screw feeding responses during gravimetric feeding. Twelve divergent raw materials were processed over longer periods using a GEA Compact Feeder integrated in a continuous direct compression line (ConsiGma™ CDC-50). The resulting gravimetric feeding responses were combined with the material properties and process settings into an overall PLS model. The model elucidated the impact of the material descriptors for density; powder flow; particle size; compressibility; permeability and wall friction angle on the feeding process. Furthermore, long-term processing of the materials exhibited challenges related to the processability and refill consistency where a significant impact of the compressibility and cohesive/adhesive properties of the materials was observed. Overall, this approach provided insights into the feasibility of long-term continuous feeding which is not possible through 'short-term' feeding trials. Additionally, throughout this study, the need for material-specific adjustments of the feeding and refill equipment was highlighted.

The effect of binder types on the breakage and drying behavior of granules in a semi-continuous fluid bed dryer after twin screw wet granulation.

Current study investigated the effect of different binder types on the granule drying process and the granule breakage behavior in a semi-continuous fluid bed dryer integrated in the C25 ConsiGma-system. The studied binders (i.e. hydroxypropyl pea starch, hydroxypropyl methylcellulose E15, polyvinylpyrrolidone K12, and starch octenyl succinate CO 01) required different liquid amounts to produce similar granule quality. These different liquid requirements were translated into different drying conditions for each binder to result in sufficiently dry granules at the end of a drying cycle. By comparing the size distribution of the granules before entering and after exiting the fluid bed dryer, granule breakage could be evaluated. No effect of the binder type on the granule breakage during drying was observed. However, differences in granule breakage were observed for the binders when processed with the horizontal set-up of the C25 system, as granule breakage during pneumatic transport depended on the binder type. Only one binder (hydroxypropyl pea starch) allowed to avoid granule breakage during the entire process. Furthermore, this research showed that the drying process was mainly steered by the liquid requirements for granulation, and that these liquid requirements depended on the binder used.

Impact of blend properties and process variables on the blending performance.

In this study, quantitative relationships were established between blend properties, process settings and blending responses via multivariate data-analysis. Four divergent binary blends were composed in three different ratios and processed at various throughputs and impeller speeds. Additionally, different impeller configurations were tested to see their impact on the overall blending performance. During each run, feeder mass flows were compared with the API concentration (BU) in order to investigate the dampening potential of the blender. The blender hold-up mass (HM), mean residence time (MRT), strain on the powder (#BP) and BU variability (RSDBU) were determined as blending descriptors and analyzed via PLS-regression. This elucidated the correlation between process settings (i.e. throughput and impeller speed) and blending responses, as well as the impact of blend properties on MRT and RSDBU. Furthermore, the study revealed that HM does not need to be in steady state conditions to assure a stable BU, while it became clear that long/large feeder deviations can only be dampened by the blender when using dedicated impeller configurations. Overall, this study demonstrated the generic application of the blender, while the developed PLS models could be used to predict the blender performance based on the blend properties.

Evaluation of torque as an in-process control for granule size during twin-screw wet granulation.

The potential of torque as in-process control (IPC) to monitor granule size in twin-screw wet granulation (TSG) was investigated. An experimental set-up allowing the collection of granules at four different locations (i.e., in the wetting zone, after the first and second kneading zone and at the end of the granulator) of the granulator screws was used to determine the change in granule size, granule temperature and the contribution of each compartment to the overall torque for varying screw speed, mass feed rate and liquid-to-solid ratio. The only observed correlation was between the granule size and torque increase after the first kneading zone because the torque increase was an indication of the degree in granule growth which was consistently observed with all applied granulation process parameters. No correlation was observed in the other locations as changes of torque were accompanied to either granule breakage and/or growth. Moreover, torque increase was correlated to higher granule temperature, suggesting that energy put into the granulator was partly used to heat up the material being processed and explains additionally the lack of correlation between granule size and torque. Therefore, this study showed that torque could not be used as IPC to monitor granule size during TSG.

Determination of a quantitative relationship between material properties, process settings and screw feeding behavior via multivariate data-analysis.

In this study, a quantitative relationship between material properties, process settings and screw feeding responses of a high-throughput feeder was established via multivariate models (PLS). Thirteen divergent powders were selected and characterized for 44 material property descriptors. During volumetric feeder trials, the maximum feed capacity (FCCmax), the relative standard deviation on the maximum feed capacity (RSDFCmax), the short term variability (STRSD) and feed capacity decay (FCdecay) were determined. The gravimetric feeder trials generated values for the mass flow rate variability (RSDLC), short term variability (STRSD) and refill responses (Vrefill and RSDrefill). The developed PLS models elucidated that the material properties and process settings were clearly correlated to the feeding behavior. The extended volumetric feeder trials pointed out that there was a significant influence of the chosen screw type and screw speed on the feeding process. Furthermore, the process could be optimized by reducing the feeding variability through the application of optimized mass flow filters, high frequency vibrations, independent agitator control and optimized top-up systems. Overall, the models could allow the prediction of the feeding performance for a wide range of materials based on the characterization of a subset of material properties greatly reducing the number of required feeding experiments.

Extrusion-based 3D printing of oral solid dosage forms: Material requirements and equipment dependencies.

Extrusion-based 3D printing is steadily gaining importance as a manufacturing technique due to its flexibility and wide range of possible end-products. In the medical field, the technique is being exploited for a variety of applications and one of these is the production of personalised medicines. However, despite many proof-of-concept studies, more thorough insights in the production technique itself and the required material properties are needed before 3D printing can be fully exploited in a hospital or pharmacy setting. This research aims at clarifying the complex interplay between material properties, process parameters and printer-dependent variables. A variety of different polymers and polymer-drug blends were extruded (diameter 1.75±0.05 mm) and characterised in terms of mechanical, thermal and rheological properties. These properties, together with the processing temperature, printing speeds and different nozzle diameters of the 3D printer were linked to the quality of the end-product. Different failure mechanisms (mechanical, thermal) were assessed. Decisive material parameters (e.g. cross-over point) for optimal printing behaviour and the importance of printer construction (nozzle diameter) were clarified. In general, this study offers insight into the 3D printing process and will help to speed up future pharmaceutical formulation development for printlets.

Screening of pharmaceutical polymers for extrusion-Based Additive Manufacturing of patient-tailored tablets.

The main objective of this work was to explore the potential of coupling hot-melt extrusion (HME) to Fused Filament Fabrication (FFF), also known as Extrusion-Based Additive Manufacturing (EBAM) or 3D Printing, in order to manufacture 3D printed tablets with different release behavior from plasticizer-free filament matrices. The suitability of different thermoplastic polymers towards FFF was investigated, and a link between the mechanical properties of filaments produced by HME and the feeding performance into the FFF printer was established. Model drugs with different aqueous solubility (metoprolol tartrate and theophylline anhydrous) were processed with hydrophilic and hydrophobic polymers, and the influence of the formulation, drug concentration and applied process settings on the release kinetics was investigated. Filaments with up to 40% drug load were successfully extruded with a smooth surface and a diameter of 1.75 ± 0.05 mm. However, filaments with high brittleness and low toughness were broken by the feeding gears. In contrast, none of the filaments were squeezed aside by the gears, which indicated that they were sufficiently stiff as indicated by the high Young's moduli of all formulations. For all formulations, the release from the tablets with 50% infill degree was faster as compared to the tablets with 100% infill degree. Theophylline (20% w/w) release from Kollicoat® IR matrix was completed within 40 min from 50% infill tablets. In contrast, 80% metoprolol tartrate was released from the hydrophobic Capa® 6506 polymer within 24hrs from 50% infill 3D tablets containing 40% w/w MPT.

Influence of binder attributes on binder effectiveness in a continuous twin screw wet granulation process via wet and dry binder addition.

The effect of a wide variety of binders on the quality of granules produced via continuous twin screw wet granulation was studied. Anhydrous dicalcium phosphate was used as poorly soluble filler and was granulated applying dry or wet addition of binders. Furthermore, dry and wet binder characteristics were determined and linked to the binder effectiveness. PVA 4-88 and starch octenyl succinate exhibited the lowest granule friability at low liquid-to-solid ratios, i.e. the highest binder effectiveness, which was attributed to fast binder activation based on the fast wetting kinetics of the binder, to efficient wetting of DCP particles, and to good spreading in the powder bed. The performance of wettability measurements in an early formulation development stage is therefore considered highly important. Additionally, an increased stickiness of the binder surface caused by high binder viscosity and slow dissolution kinetics also positively influenced the binder effectiveness. In conclusion, this study revealed which binder attributes have a critical impact on the granulation process of dicalcium phosphate. Additionally, dry binder addition proved successful for creation of high quality granules.

In-line temperature measurement to improve the understanding of the wetting phase in twin-screw wet granulation and its use in process development.

Wetting is the initial stage of wet granulation processes during which the first contact between the powder and the liquid occurs. Wetting is a critical step to allow granule growth and consolidation, but also to ensure uniform active pharmaceutical ingredient (API) distribution over all granule size fractions. A physical understanding of the wetting stage is therefore crucial to design a robust granulation process. In twin-screw granulation, wetting is physically separated from granule consolidation, growth, breakage and attrition. The present study used this particularity to investigate the wetting step in such a way that the fundamental mechanisms governing the wetting can be linked and understood. A modified granulator barrel was used allowing the collection of granules immediately after the wetting. A low drug-loaded pharmaceutical formulation containing a poorly soluble and poorly wettable API was used for this investigation. Granules obtained after the wetting zone were analysed for granule size distribution, API distribution over the different size fractions and granule temperature. It was found that "wetting efficiency" (i.e., fraction of powder being nucleated during the wetting stage) could be predicted using an energy balance based on in-line measurement of the granule temperature. Wetting efficiency could moreover be linked to final granule quality attributes (i.e., granule size distribution) at the outlet of the granulator. It was further demonstrated that granule growth and consolidation could only be achieved when complete wetting was achieved in the wetting zone of the granulator. This study suggested a methodology based on in-line temperature measurements to quickly determine wetting efficiency. The described methodology could therefore be used as a tool to gain more fundamental understanding of the wetting stage during twin-screw granulation as well as to define suitable formulation and process ranges for further granulation process development.

Viscosity of API/fatty acid suspensions: Pitfalls during analysis.

This article describes how to obtain reliable data during rheological analysis of active pharmaceutical ingredient/fatty acid suspensions. These materials are specifically used for prilling, an innovative pharmaceutical technique for the production of a multiparticulate dosage form. Nevertheless, presented guidelines are applicable for a wide range of pharmaceutical suspensions. Reliable rheological results can only be obtained when being aware of artefacts, such as a non-continuous medium, sedimentation, apparent wall slip and protrusion flow. To comply with the continuum hypothesis at high phase volumes (≥25% w/w), the required gap-to-particle-size ratio may be larger than the generally accepted 10:1 ratio. Reproducible flow curves that are not disturbed by sedimentation during sample analysis can be obtained faster by varying the shear rate stepwise from high to low values. While apparent wall slip (at low shear rates) can be prevented via serrated instead of smooth plates, protrusion flow (at high shear rates) during measurements with serrated plates results in non-reliable data. Therefore, in general, high viscous suspensions with yield stress can be analysed with serrated plates, while low viscous suspensions without yield stress should be analysed with geometries having smooth surfaces. By following these guidelines, accurate rheological properties of pharmaceutical suspensions can be obtained.

Delta-mannitol to enable continuous twin-screw granulation of a highly dosed, poorly compactable formulation.

In current study, it was investigated if the moisture-mediated polymorphic transition from δ- to ß-mannitol during twin screw granulation (TSG) also took place in high drug loaded formulations and if the specific granule morphology associated with the polymorphic transition could enable tableting of granules comprising 75% paracetamol, a poorly compactable drug. Experiments were performed on an integrated continuous manufacturing line, including a twin screw granulator, fluid bed dryer, mill and tablet press. The polymorphic transition of δ- to ß-mannitol was observed during twin screw granulation and granules exhibited the needle-shaped morphology, typical of this transition. TSG at low liquid-to-solid (L/S) ratios and use of polyvinylpyrrolidone or hydroxypropylmethylcellulose as binders inhibited the polymorphic transition, whereas screw speed, drying time, drying temperature and airflow did not affect the solid state of mannitol in the granules. Without binder and despite the high paracetamol drug load in the formulation, limited breakage and attrition was observed during drying and milling. In contrast to granules manufactured from a formulation containing paracetamol/ß-mannitol which could not be tableted due to extensive capping, granules prepared from a paracetamol/δ-mannitol formulation showed good tabletability. In conclusion, δ-mannitol is a promising TSG excipient, especially for high drug-loaded formulations with poor tabletability.

Recent progress in continuous manufacturing of oral solid dosage forms.

Continuous drug product manufacturing is slowly being implemented in the pharmaceutical industry. Although the benefits related to the quality and cost of continuous manufacturing are widely recognized, several challenges hampered the widespread introduction of continuous manufacturing of drug products. Current review presents an overview of state-of-the art research, equipment, process analytical technology implementations and advanced control strategies. Additionally, guidelines and regulatory viewpoints on implementation of continuous manufacturing in the pharmaceutical industry are discussed.