Experimental and numerical characterization of screw elements used in twin-screw extrusion.

Hot melt extrusion by a co-rotating twin screw extruder is an important process in the pharmaceutical industry. Especially for quality by design aspects, a comprehensive process understanding is indispensable. The performance of conveying elements was determined as critical process parameter, and therefore an experimental and numerical framework was developed to analyze and compare variations. A test rig capable of measuring volume flow, pressure and torque with high accuracy and precision was designed and built. The 3D simulation was performed using computational fluid dynamics (CFD). A stationary model with impulse transmission and an apparent motion of the screws was applied. The experimental data were fitted to the model of Pawlowski, and parameters for the pressure (A1, A2) and power characteristics (B1, B2) were determined. Good agreement between experimental data and the model was observed. The simulation was significantly faster compared to common methods, and the results were consistent with the literature. Systematic investigations of a native and worn screw were performed with CFD resulting in a transport capacity increase and a pressure build up decrease for all tested screw elements. An experimental and simulation setup was generated to assess the performance of co-rotating twin screw elements. The experiments provided high-quality data, and the simulations exhibited high flexibility with low computational effort.

Insights into the Mechanism of Enhanced Dissolution in Solid Crystalline Formulations.

Solid dispersions are a promising approach to enhance the dissolution of poorly water-soluble drugs. Solid crystalline formulations show a fast drug dissolution and a high thermodynamic stability. To understand the mechanisms leading to the faster dissolution of solid crystalline formulations, physical mixtures of the poorly soluble drugs celecoxib, naproxen and phenytoin were investigated in the flow through cell (apparatus 4). The effect of drug load, hydrodynamics in the flow through cell and particle size reduction in co-milled physical mixtures were studied. A carrier- and drug-enabled dissolution could be distinguished. Below a certain drug load, the limit of drug load, carrier-enabled dissolution occurred, and above this value, the drug defined the dissolution rate. For a carrier-enabled behavior, the dissolution kinetics can be divided into a first fast phase, a second slow phase and a transition phase in between. This study contributes to the understanding of the dissolution mechanism in solid crystalline formulations and is thereby valuable for the process and formulation development.

Measuring and Modeling of Melt Viscosity for Drug Polymer Mixtures.

Melt viscosity is an essential property in pharmaceutical processes such as mixing, extrusion, fused deposition modeling, and melt coating. Measuring and modeling of the melt viscosity for drug/polymer mixtures is essential for optimization of the manufacturing process. In this work, the melt viscosity of nine formulations containing the drug substances acetaminophen, itraconazole, and griseofulvin, as well as the pharmaceutical polymers Eudragit EPO, Soluplus, and Plasdone S-630, were analyzed with a rotational and oscillatory rheometer. The shear rate, temperature, and drug fraction were varied systematically to investigate their influence on viscosity. The results for the pure polymers showed typical shear-thinning behavior and are fundamental for modeling with the Carreau and Arrhenius approaches. The investigations of the viscosity of the drug/polymer mixtures resulted in a plasticizing or a filler effect, depending on the type of drug and the phase behavior. A drug shift factor was proposed to model the change in viscosity as a function of the drug fraction. On this basis, a universal model to describe the melt viscosity of drug/polymer mixtures was developed, considering shear rate, temperature, and drug fraction.

Intrinsic dissolution rate modeling for the pharmacopoeia apparatus rotating disk compared to flow channel method.

For a solid understanding of drug characteristics, in vitro measurement of the intrinsic dissolution rate is important. Hydrodynamics are often emphasized as the decisive parameter influencing the dissolution. In this study, experiments and computational fluid dynamic (CFD) simulations showed that the mixing behavior in the rotating disc apparatus causes an inhomogeneous flow field and a systematic error in the calculation of the intrinsic dissolution rate. This error is affected by both the experimental time and the velocity. Due to the rotational movement around the tablet center, commonly utilized in pharmacopeia methods, a broad variance is present with regard to the impact of fluid velocity on individual particles of the specimen surface. As this is significantly reduced in the case of uniform overflow, the flow channel is recommended for investigating the dissolution behavior. It is shown that rotating disc measurements can be compared with flow channel measurements after adjusting the measured data for the rotating disc based on a proposed, representative Reynolds number and a suggested apparatus-dependent correction factor. Additionally, modeling the apparatus-independent intrinsic dissolution rate for different temperatures in the rotating disc apparatus is possible using the adapted Levich's equation.

Composition Dependency of the Flory-Huggins Interaction Parameter in Drug-Polymer Phase Behavior.

An innovative strategy to address recent challenges in the oral administration of poorly soluble drugs is the formulation of amorphous solid dispersions (ASDs), where the drug is dissolved in a highly soluble carrier polymer. Therefore, special knowledge of the drug-polymer phase behavior is essential for an effective product and process design, accelerating the introduction of novel efficacious ASD products. Flory-Huggins theory can be applied to model solubility temperatures of crystalline drugs in carrier polymers over the drug fraction. However, predicted solubility temperatures lack accuracy in cases of strong drug/polymer interactions that are not represented in the Flory-Huggins lattice model. Within this study, a modeling strategy is proposed to improve the predictive power through an extension of the Flory-Huggins interaction parameter by a correlation with the drug fraction. Therefore, the composition dependency of the Flory-Huggins interaction parameter was evaluated experimentally for various drug-polymer formulations that cover a wide variety of drug and polymer characteristics regarding molecular weights, glass transition temperatures and melting temperatures, as well as drug-polymer interactions of different strengths and effects. The extended model was successfully approved for nine exemplary ASD formulations containing the drugs acetaminophen, itraconazole, and griseofulvine, as well as the following polymers: basic butylated methacrylate copolymer, Soluplus®, and vinylpyrrolidone/vinyl acetate copolymer. A high correlation between the predicted solubility temperatures and experimental and literature data was found, particularly at low drug fractions, since the model accounts for composition dependent drug-polymer interactions.

UV/Vis spectroscopy as an in-line monitoring tool for tablet content uniformity.

Continuous manufacturing provides advantages compared to batch manufacturing and is increasingly gaining importance in the pharmaceutical industry. In particular, the implementation of tablet processes in continuous plants is an important part of current research. For this, in-line real-time monitoring of product quality through process analytical technology (PAT) tools is crucial. This study focuses on an in-line UV/Vis spectroscopy method for monitoring the active pharmaceutical ingredient (API) content in tablets. UV/Vis spectroscopy is particularly advantageous here, because it allows univariate data analysis without complex data processing. Experiments were conducted on a rotary tablet press. The tablets consisted of 7- 13 wt% theophylline monohydrate as API, lactose monohydrate and magnesium stearate. Two tablet production rates were investigated, 7200 and 20000 tablets per hour. The UV/Vis probe was mounted at the ejection position and measurements were taken on the tablet sidewall. Validation was according to ICH Q2 with respect to specificity, linearity, precision, accuracy and range. The specificity for this formulation was proven and linearity was sufficient with coefficients of determination of 0.9891 for the low throughput and 0.9936 for the high throughput. Repeatability and intermediate precision were investigated. Both were sufficient, indicated by coefficients of variations with a maximum of 6.46% and 6.34%, respectively. The accuracy was evaluated by mean percent recovery. This showed a higher accuracy at 20000 tablets per hour than 7200 tablets per hour. However, both throughputs demonstrate sufficient accuracy. Finally, UV/Vis spectroscopy is a promising alternative to the common NIR and Raman Spectroscopy.

Material Transport Characteristics in Planetary Roller Melt Granulation.

Melt granulation for improving material handling by modifying particle size distribution offers significant advantages compared to the standard methods of dry and wet granulation in dust reduction, obviating a subsequent drying step. Furthermore, current research in pharmaceutical technology aims for continuous methods, as these have an enhanced potential to reduce product quality fluctuations. Concerning both aspects, the use of a planetary roller granulator is consequential. The process control with these machines benefits from the enhanced ratio of heated surface to processed volume, compared to the usually-applied twin-screw systems. This is related to the unique concept of planetary spindles flowing around a central spindle in a roller cylinder. Herein, the movement pattern defines the transport characteristics, which determine the energy input and overall processing conditions. The aim of this study is to investigate the residence time distribution in planetary roller melt granulation (PRMG) as an indicator for the material transport. By altering feed rate and rotation speed, the fill level in the granulator is adjusted, which directly affects the average transport velocity and mixing volume. The two-compartment model was utilized to reflect these coherences, as the model parameters symbolize the sub-processes of axial material transport and mixing.

Predicting self-diffusion coefficients in semi-crystalline and amorphous solid dispersions using free volume theory.

The self-diffusion coefficient of active ingredients (AI) in polymeric solid dispersions is one of the essential parameters for the rational formulation design in life sciences. Measuring this parameter for products in their application temperature range can, however, be difficult to realise and time-consuming (due to the slow kinetics of diffusion). The aim of this study is to present a simple and time-saving platform for predicting the AI self-diffusivity in amorphous and semi-crystalline polymers on the basis of a modified version of Vrentas' and Duda's free volume theory (FVT) [A. Mansuri, M. Völkel, T. Feuerbach, J. Winck, A.W.P. Vermeer, W. Hoheisel, M. Thommes, Modified free volume theory for self-diffusion of small molecules in amorphous polymers, Macromolecules. (2023)]. The predictive model discussed in this work requires pure-component properties as its input and covers the approximate temperature range of T < 1.2 Tg, the whole compositional range of the binary mixtures (as long as a molecular mixture is present), and the whole crystallinity range of the polymer. In this context, the self-diffusion coefficients of the AIs imidacloprid, indomethacin, and deltamethrin were predicted in polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate, polystyrene, polyethylene, and polypropylene. The results highlight the profound importance of the kinetic fragility of the solid dispersion on the molecular migration; a property which in some cases might entail higher self-diffusion coefficients despite an increase in the molecular weight of the polymer. We interpret this observation within the context of the theory of heterogeneous dynamics in glass-formers [M.D. Ediger, Spatially heterogeneous dynamics in supercooled liquids, Annu. Rev. Phys. Chem. 51 (2000) 99-128] by attributing it to the stronger presence of "fluid-like" mobile regions in fragile polymers offering facilitated routes for the AI diffusion within the dispersion. The modified FVT further allows for identifying the influence of some structural and thermophysical material properties on the translational mobility of AIs in binary dispersions with polymers. In addition, estimates of self-diffusivity in semi-crystalline polymers are provided by further accounting for the tortuosity of the diffusion paths and the chain immobilisation at the interface of the amorphous and crystalline phases.

Predicting Residence Time and Melt Temperature in Pharmaceutical Hot Melt Extrusion.

Hot-melt extrusion is increasingly applied in the pharmaceutical area as a continuous processing technology, used to design custom products by co-processing drugs together with functional excipients. In this context, the residence time and processing temperature during extrusion are critical process parameters for ensuring the highest product qualities, particularly of thermosensitive materials. Within this study, a novel strategy is proposed to predict the residence time distribution and melt temperature during pharmaceutical hot-melt extrusion processes based on experimental data. To do this, an autogenic extrusion mode without external heating and cooling was applied to process three polymers (Plasdone S-630, Soluplus and Eudragit EPO) at different specific feed loads, which were set by the screw speed and the throughput. The residence time distributions were modeled based on a two-compartment approach that couples the behavior of a pipe and a stirred tank. The throughput showed a substantial effect on the residence time, whereas the influence of the screw speed was minor. On the other hand, the melt temperatures during extrusion were mainly affected by the screw speed compared to the influence of the throughput. Finally, the compilation of model parameters for the residence time and the melt temperature within design spaces serve as the basis for an optimized prediction of pharmaceutical hot-melt extrusion processes.

Molecular Dynamics and Diffusion in Amorphous Solid Dispersions Containing Imidacloprid.

The main goal of this study is to develop an experimental toolbox to estimate the self-diffusion coefficient of active ingredients (AI) in single-phase amorphous solid dispersions (ASD) close to the glass transition of the mixture using dielectric spectroscopy (DS) and oscillatory rheology. The proposed methodology is tested for a model system containing the insecticide imidacloprid (IMI) and the copolymer copovidone (PVP/VA) prepared via hot-melt extrusion. For this purpose, reorientational and the viscoelastic structural (α-)relaxation time constants of hot-melt-extruded ASDs were obtained via DS and shear rheology, respectively. These were then utilized to extract the viscosity as well as the fragility index of the dispersions as input parameters to the fractional Stokes-Einstein (F-SE) relation. Furthermore, a modified version of Almond-West (AW) formalism, originally developed to describe charge diffusion in ionic conductors, was exercised on the present model system for the estimation of the AI diffusion coefficients based on shear modulus relaxation times. Our results revealed that, at the calorimetric glass-transition temperature (Tg), the self-diffusion coefficients of the AI in the compositional range from infinite dilution up to 60 wt % IMI content lied in the narrow range of 10-18-10-20 m2 s-1, while the viscosity values of the dispersions at Tg varied between 108 Pa s and 1010 Pa s. In addition, the phase diagram of the IMI-PVP/VA system was determined using the melting point depression method via differential scanning calorimetry (DSC), while mid-infrared (IR) spectroscopy was employed to investigate the intermolecular interactions within the solid dispersions. In this respect, the findings of a modest variation in melting point at different compositions stayed in agreement with the observations of weak hydrogen bonding interactions between the AI and the polymer. Moreover, IR spectroscopy showed the intermolecular IMI-IMI hydrogen bonding to have been considerably suppressed, as a result of the spatial separation of the AI molecules within the ASDs. In summary, this study provides experimental approaches to study diffusivity in ASDs using DS and oscillatory rheology, in addition to contributing to an enhanced understanding of the interactions and phase behavior in these systems.

Characterizing Phase Separation of Amorphous Solid Dispersions Containing Imidacloprid.

Amorphous-Amorphous phase separation (AAPS) is an important phenomenon that can impede the performance of amorphous solid dispersions (ASDs). The purpose of this study was to develop a sensitive approach relying on dielectric spectroscopy (DS) to characterize AAPS in ASDs. This includes detecting AAPS, determining the size of the active ingredient (AI) discrete domains in the phase-separated systems, and accessing the molecular mobility in each phase. Using a model system consisting of the insecticide imidacloprid (IMI) and the polymer polystyrene (PS), the dielectric results were further confirmed by confocal fluorescence microscopy (CFM). The detection of AAPS by DS was accomplished by identifying the decoupled structural (α-)dynamics of the AI and the polymer phase. The α-relaxation times corresponding to each phase correlated reasonably well with those of the pure components, implying nearly complete macroscopic phase separation. Congruent with the DS results, the occurrence of the AAPS was detected by means of CFM, making use of the autofluorescent property of IMI. Oscillatory shear rheology and differential scanning calorimetry (DSC) detected the glass transition of the polymer phase but not that of the AI phase. Furthermore, the otherwise undesired effects of interfacial and electrode polarization, which can appear in DS, were exploited to determine the effective domain size of the discrete AI phase in this work. Here, stereological analysis of CFM images probing the mean diameter of the phase-separated IMI domains directly stayed in reasonably good agreement with the DS-based estimates. The size of phase-separated microclusters showed little variation with AI loading, implying that the ASDs have presumably undergone AAPS upon manufacturing. DSC provided further support to the immiscibility of IMI and PS, as no discernible melting point depression of the corresponding physical mixtures was detected. Moreover, no signatures of strong attractive AI-polymer interactions could be detected by mid-infrared spectroscopy within this ASD system. Finally, dielectric cold crystallization experiments of the pure AI and the 60 wt % dispersion revealed comparable crystallization onset times, hinting at a poor inhibition of the AI crystallization within the ASD. These observations are in harmony with the occurrence of AAPS. In conclusion, our multifaceted experimental approach opens new venues for rationalizing the mechanisms and kinetics of phase separation in amorphous solid dispersions.

In-line monitoring of solid dispersion preparation in small scale extrusion based on UV-vis spectroscopy.

The poor solubility of a large number of active pharmaceutical ingredients (APIs) is a major challenge in pharmaceutical research. Therefore, the extrusion of amorphous solid dispersions (ASDs) is one promising approach to enhance the dissolution rate by molecularly dissolving the API in an amorphous carrier polymer. During ASD extrusion, crucial parameters as the dissolution of the API in the carrier polymer need to be monitored. Within this study, a small scale twin screw extruder was coupled with special ColVisTec UV-vis probes that are characterized by their small dimensions. This setup enables a systematic formulation design and optimization based on in-line monitoring of drug dissolution using small material quantities. In fact, sample quantities of about 5 mg were evaluated for each measurement, representing 50% of the material inside the die. The amount of undissolved drug particles was determined based on the lightness of the extrudates. It was shown that the temperature has a significant effect on the drug dissolution in the polymer. Furthermore, complete drug dissolution was shifted to lower temperatures if higher residence times were applied. Based on the courses of lightness, regime maps were modeled that specify the process conditions where ASDs are successfully manufactured.

Modeling of Particle Dissolution Behavior Using a Geometrical Phase-Field Approach.

Material dissolution is a critical attribute of many products in a wide variety of industries. The idealized view of dissolution through established prediction tools should be reconsidered because the number of new substances with low aqueous solubility is increasing. Due to this, a fundamental understanding of the dissolution process is desired. The aim of this study was to develop a tool to predict crystal dissolution performance based on experimentally measurable physical parameters. A numerical simulation, called the phase-field method, was used to simultaneously solve the time evolution of the phase and concentration fields of dissolving particles. This approach applies to diffusion-limited as well as surface reaction-limited systems. The numerical results were compared to analytical solutions, and the influence of particle shape and interparticle proximity on the dissolution process was numerically investigated. Dissolution behaviors of two different substances were modeled. A diffusion-limited model compound, xylitol, with a high aqueous solubility and a surface reaction-limited model compound, griseofulvin, with a low aqueous solubility were chosen. The results of the simulations demonstrated that phase-field modeling is a powerful approach for predicting the dissolution behaviors of pure crystalline substances.

Predicting Throughput and Melt Temperature in Pharmaceutical Hot Melt Extrusion.

Even though hot melt extrusion (HME) is a commonly applied process in the pharmaceutical area, determination of the optimal process parameters is demanding. The goal of this study was to find a rational approach for predetermining suitable extrusion parameters, with a focus on material temperature and throughput. A two-step optimization procedure, called scale-independent optimization strategy (SIOS), was applied and developed further, including the use of an autogenic extrusion mode. Three different polymers (Plasdone S-630, Soluplus, and Eudragit EPO) were considered, and different optimal process parameters were assessed. The maximum barrel load was dependent on the polymers' bulk density and the extruder size. The melt temperature was influenced by the screw speed and the rheological behavior of the polymer. The melt viscosity depended mainly on the screw speed and was self-adjusted in the autogenic extrusion. A new approach, called SIOS 2.0, was suggested for calculating the extrusion process parameters (screw speed, melt temperature and throughput) based on the material data and a few extrusion experiments.

Factors Influencing the Crystallization-Onset Time of Metastable ASDs.

In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that the long-term stability of ASDs strongly depends on the storage conditions (relative humidity, temperature), the manufacturing methods, and the resulting particle sizes. In this work, ASDs composed of the model APIs Griseofulvin (GRI) or Itraconazole (ITR) and the polymers poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) or Soluplus® were manufactured via spray drying and hot-melt extrusion. Each API/polymer combination was manufactured using the two manufacturing methods with at least two different API loads and two particle-size distributions. It was a priori known that these ASDs were metastable and would crystallize over time, even in the dry stage. The amount of water absorbed by the ASD from humid air (40 °C/75% relative humidity), the solubility of the API in the ASD at humid conditions, and the resulting glass-transition temperature were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor approach, respectively. The onset of crystallization was determined via periodic powder X-ray diffraction (PXRD) measurements. It was shown that simple heuristics such as "larger particles always crystallize later than smaller particles" are correct within one manufacturing method but cannot be transferred from one manufacturing method to another. Moreover, amorphous phase separation in the ASDs was shown to also influence their crystallization kinetics. Counterintuitively, phase separation accelerated the crystallization time, which could be explained by the glass-transition temperatures of the evolving phases.

A novel approach of external lubrication in a rotary tablet press using electrostatics.

PURPOSE: In powder compaction on rotary tablet presses, the addition of a lubricant is normally mandatory. However, the typical internal lubrication method tends toward overlubrication, resulting in an alteration of the critical quality attributes of the product. In this study, the feasibility of an external lubrication system only using electrostatics for the application was investigated. METHODS: Three well-established lubricants were analyzed regarding their ability to accumulate and retain charge. In subsequent tableting experiments, the impact of different lubrication methods on critical quality attributes and process parameters was investigated. RESULTS: Due to material characteristics, the charge on magnesium stearate particles was most stable over time. The application of this lubricant on the punches via external lubrication with electrostatic forces resulted in a significant reduction of the ejection forces. Furthermore, the tensile strength of the tablets produced in these trials was significantly higher compared to tablets that were produced with internal lubrication. CONCLUSION: The external lubrication method with an electrostatically charged lubricant is a promising method for reducing both the necessary amount of lubricant and the impact of the lubricant on the product.

Residence time and mixing capacity of a rotary tablet press feed frame.

PURPOSE: Most rotary tablet presses contain a feed frame to provide a continuous powder flow and to feed powder into the dies. The wide residence time distribution (RTD) of these feed frames is problematic, because it negatively affects material traceability in continuous manufacturing. In a rotary tablet press, different machine settings influence the RTD, which is characterized by the mean and the width of the distribution. This study focused on the effects of the rotational speed of the feed frame paddles and the rotary tablet press throughput on the RTD. METHODS: An in-line UV/Vis measurement method was developed for determining the RTD in the feed frame. A model based on a plug flow and a continuous stirred tank reactor was adapted to model the experimentally determined RTDs. Finally, the mixing capacity of a feed frame was evaluated and correlated with a model parameter of the RTD. RESULTS: Overall, the developed UV/Vis measurement method was suitable and could be used to obtain process information regarding content uniformity in real time. The experimentally-determined RTDs were described well by fitting an inverse mixing and a transport time. In addition, a correlation between the location and the shape of measured RTDs and tablet press throughput was found. In contrast, rotational feed frame paddle speed did not affect the RTDs. Split-feeding experiments indicated the mixing capacity of the rotary tablet press feed frame. CONCLUSION: The inverse mixing time can be used as an initial indicator for estimating the mixing capacity.

Design and Characterization of a Screw Extrusion Hot-End for Fused Deposition Modeling.

The filament is the most widespread feedstock material form used for fused deposition modeling printers. Filaments must be manufactured with tight dimensional tolerances, both to be processable in the hot-end and to obtain printed objects of high quality. The ability to successfully feed the filament into the printer is also related to the mechanical properties of the filament, which are often insufficient for pharmaceutically relevant excipients. In the scope of this work, an 8 mm single screw hot-end was designed and characterized, which allows direct printing of materials from their powder form and does not require an intermediate filament. The capability of the hot-end to increase the range of applicable excipients to fused deposition modeling was demonstrated by processing and printing several excipients that are not suitable for fused deposition modeling in their filament forms, such as ethylene vinyl acetate and poly(1-vinylpyrrolidone-co-vinyl acetate). The conveying characteristic of the screw was investigated experimentally with all materials and was in agreement with an established model from literature. The complete design information, such as the screw geometry and the hot-end dimensions, is provided in this work.

Determination of Inherent Dissolution Performance of Drug Substances.

The dissolution behavior of novel active pharmaceutical ingredients (API) is a crucial parameter in drug formulation since it frequently affects the drug release. Generally, a distinction is made between surface-reaction- and diffusion-controlled drug release. Therefore, dissolution studies such as the intrinsic dissolution test defined in the pharmacopeia have been performed for many years. In order to overcome the disadvantages of the common intrinsic dissolution test, a new experimental setup was developed within this study. Specifically, a flow channel was designed and tested for measuring the mass transfer from a flat, solid surface dissolving into a fluid flowing over the surface with well-defined flow conditions. A mathematical model was developed that distinguishes between surface-reaction- and diffusion-limited drug release based on experimental data. Three different drugs-benzocaine, theophylline and griseofulvin-were used to investigate the mass flux during dissolution due to surface reaction, diffusion and convection kinetics. This new technique shows potential to be a valuable tool for the identification of formulation strategies.

Elucidation of mass transfer mechanisms in pellet formation by spheronization.

Previously published mechanisms of pellet formation during extrusion-spheronization include a transfer of material between different granules. This research aimed to specify the origin of this transfered mass, enabling further insight into the extrusion-spheronization process. Granules of various diameters were rounded simultaniously in a spheronizer to ascertain if mass transfer between smaller and larger granules is truly in balance, or if mass transfer from smaller to larger granules is preferred. Granules were also marked with a fluorescent tracer to enable quantification of mass transfer. By using differently sized and shaped granules as starting material, different modes of mass transfer were investigated. Samples were taken after various process durations to investigate the kinetics of the tranfer mechanism. It was found that both small and large granules dispense and receive mass during spheronization. In general, small granules increase their size, while large granules maintain their size or show a slight size decrease, resulting in the particularly narrow monomodal size distribution.