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This book describes the latest research on producing functional particles using spray processes. The authors detail micro level elementary processes and phase boundaries, process analysis scaling and modeling, and macro level process functions and particle properties. They include numerical simulations and particulars of experiments for deriving process conditions for particle production.



Process-Spray Micro Scale: Elementary Processes at Phase Boundaries


Chapter 1. Investigation of Elementary Processes of Non-Newtonian Droplets Inside Spray Processes by Means of Direct Numerical Simulation

Binary droplet collisions play an important role as an essential elementary process in sprays. They significantly influence the droplet size distribution. In order to give an improved prediction of the outcome of droplet collisions, understanding of the influence of the liquid rheology on the collisions as well as on the flow dynamics inside the colliding droplets is necessary. In this work, we have investigated binary droplet collisions by means of Direct Numerical Simulation (DNS) of two-phase incompressible Navier–Stokes equations using the Volume-of-Fluid (VOF) code Free Surface 3D (FS3D). A pivotal aim of the study is to derive mechanistic models for the outcome of collisions which can be used for scale-reduced simulations such as Euler–Euler and Euler–Lagrange simulations. In order to reach this goal, we have investigated various kinds of collisions, such as collisions of shear-thinning, non-isoviscous, and viscoelastic droplets. We have also developed and implemented various numerical algorithms to overcome the numerical difficulties in simulating different kinds of collisions.
In droplet collisions at high Weber numbers, extremely thin liquid lamellae appear. These lamellae must be reproduced in the numerical simulation in a physically meaningful way. A stabilization algorithm is therefore developed to prevent the lamellae from rupture without restrictions on the mobility and deformability of lamellae.
DNS of collisions of shear-thinning droplets show that almost all viscous dissipation occurs during the initial phase of the collision. Because of this, an effective constant viscosity can be found which leads to the same collision dynamics as with shear-thinning viscosity. This effective viscosity can be found both for head-on and off-center collisions and can be determined from simulation of just the initial phase of the collisions.
In order to simulate the collisions of droplets with unequal viscosity, an extension of the VOF method has been made by solving an additional transport equation to obtain the polymer mass fraction distribution inside the collision complex. To capture the delayed coalescence observed in experiment, a coalescence suppression algorithm has been developed. The results obtained in this way agree well with the experiment and give a deep insight into the hydrodynamic penetration and encapsulation processes.
To simulate viscoelastic two-phase flow problems, the VOF method has been extended to capture the rheological properties of the Oldroyd-B fluid. To alleviate the High Weissenberg Number Problem in the simulation of viscoelastic flow, stabilization approaches have been adapted and implemented in FS3D. The simulation results show that the viscoelastic effect is reflected in the oscillation process during the collision, and the elasticity restrains the deformation of the collision complex.
A mechanistic model, based on the model developed by Roisman et al. [26], has been extended by treating the evolution of lamella thickness and the dependence of the lamella thickness on the radius separately. With this extension, the model can predict the head-on collisions with significant influence of viscosity. The model parameters are gained by simulation of the initial phase of the collision without requirement of fine mesh resolution. This hybrid model has the advantage of massively reduced computation time compared to full DNS (below 1 %) and shows good agreement with simulation and experiment.
Xingyuan Chen, Christian Focke, Holger Marschall, Dieter Bothe

Chapter 2. Interfacial Engineering for the Microencapsulation of Lipophilic Ingredients by Spray-Drying

The present work is based on the idea that tailoring specific structures at the interfaces of an emulsion or at the surface of a drying droplet can be used to modify or improve the functionality of microcapsules prepared by spray-drying. A top-down approach was chosen to define the required functionality of the microcapsules and to identify important physical and technical variables using quality function deployment. On this basis milk proteins were chosen as surface-active carrier matrix constituent. Process windows were defined showing that β-lactoglobulin-stabilised emulsions are physically stable during atomisation and drying. Interfacial activity and rheology of the protein-stabilised interfacial film could be improved through enzymatic hydrolysis of the protein. The presence of peptides at the oil–water interface significantly increased the stability of the encapsulated material. Functionality was also increased by either formation of β-lactoglobulin fibrils or bilayer formation with pectin as anionic counterpart for stabilisation of the interfacial protein film. Although differences in the stability of the encapsulate were observed, when using different types of pectin, no clear relationship with the molecular structure of pectin could be established. In summary, the present study clearly identifies relevant variables to tailor spray-dried particles with a physical structure suitable for the microencapsulation of lipophilic ingredients and offers a range of techniques to improve the functionality through interfacial engineering.
Stephan Drusch, Yvonne Serfert, Frederic Tamm, Hanna Kastner, Karin Schwarz

Chapter 3. Structure Formation within Spray-Dried Droplets; Mathematical Modelling of Spray Polymerisation

Spray drying is a basic operation for the manufacturing of small, tailored particles. To obtain a specific porous structure of the particles, usually considerable experimental work is needed. Within this project, we developed a novel approach for modelling single droplet drying which accounts for the morphology evolution inside the particle from first principles. The underlying physical processes affecting structure formation, especially surface tension, wetting, and primary particle interactions, are taken into account within a detailed CFD approach. Simulation of suspension drying makes it necessary to represent the evolution of many interfaces. For that reason, we used the mesh-free simulation method “Smoothed particle hydrodynamics” (SPH), which represents the continuum by interpolation points moving according to a Lagrangian point of view. To our knowledge, SPH has been applied in this field for the first time. Several adaptions to the state of the art had to be made for the application in morphogenesis modelling. For the simulation of diffusion-driven drying, a hybrid simulation method was developed: liquid and solid phases are represented by SPH-particles, whereas a standard grid-based method accounts for the surrounding gas.
Simulations of the drying of suspended particles in a liquid show how the formation of a solid crust in the first drying period is affected by the drying rate and by interaction between liquid with solid particles. During the second drying period, vaporisation takes place: We propose a simple scheme to consider vapour diffusion and boiling and are able to model the formation of a hollow sphere. The receding liquid level in a porous structure has been simulated as well. The model is able to show the effects of surface tension and contact angle on diffusion-driven drying. All simulation results are 2D only, but agree qualitatively with experimental findings. Extension of our model to 3D is straight forward, but requires code parallelisation.
Spray polymerisation can be seen as an extension of spray drying in which the solid is formed by polymerisation reactions. Literature models of spray polymerisation treat droplets as fully mixed. Mathematical models accounting for spatial resolution are lacking. Based on established droplet drying approaches, we derived a 1D model for reactive spray drying processes with special emphasis on polymerisation reactions. Polymer properties, such as the chain length distribution, are represented by moments. Using the Maxwell-Stefan diffusion approach, we derived an advanced formulation for spatial transport of moments that accounts for the low mobility of the polymer chains. The molar mass distribution of the polymer can be simulated along the radius as a function of reaction rate, transport parameters, and operation conditions. Moreover, it can be shown that, against common assumptions respecting spray polymerisation, drying and chemical reactions are rather subsequent than concurrent processes. As a consequence, polymerisation reactions are typically performed as bulk polymerisation within the spray.
Winfried Säckel, Ulrich Nieken

Chapter 4. Acoustic Levitation: A Powerful Tool to Model Spray Processes

The acoustic levitation was used as a model system for spray drying processes within DFG Project SPP1423-Process Spray to elucidate the drying behavior of single droplets and the formation of the particle morphology in more detail. The gas flow characteristics inside the levitator were analyzed with computational fluid dynamics simulations. The obtained data were validated with experimental values and showed that the evaporation behavior of levitated droplets can correspond to sprayed droplets. Different reactive and nonreactive substance systems were investigated in single droplet experiments. The influence of process parameters like gas temperature, relative humidity, and droplet size on the drying behavior and particle morphology was elucidated. It was possible to track the conversion of N-Vinyl-2-pyrrolidone in droplet polymerization by using Raman spectroscopy and subsequent principal component analysis. It was found that the first principal component corresponds to the first drying stage and describes the evaporation of water, whereas the second principal component described the polymerization. The crystallinity of the obtained PVP particles increased when temperature and humidity were decreased. The polymerization of partially neutralized acrylic acid revealed the duality of polymerization and crystallization of monomer. Regarding the particle morphology, it was found that a higher amount of sodium acrylate led to a smoother particle surface. One reason for this result is that if sodium acrylate precipitates, it defines predominantly the particle structure. Another reason for this trend in particle morphology is a lower gas pressure within the particle due to a lower polymerization rate, which leads to fewer cracks within the shell. Mannitol served as a nonreactive model system. The drying rate increased with elevated gas temperatures and smaller initial droplet diameters. These experimental results corresponded well with the simulation carried out by Grosshans et al. Additionally, a categorization of morphological properties was introduced. This shows an increasing particle roughness at high temperatures and high initial mass fractions of mannitol. At high relative humidity, metastable, supersaturated mannitol solutions were formed during the drying process.
In summary, this work presents the acoustic levitation as a powerful tool to model spray processes. Thanks to its simple setup and experimental handling, acoustic levitation can give the opportunity to elucidate the processes within single droplets for a wide range of reactive and nonreactive spray systems. It also offers a simple way to check the suitability of systems that have not been considered for spray processes yet.
M. Junk, A. H. Halfar, M. Griesing, R. Sedelmayer, J. Laackmann, L. Cepelyte, W. Pauer, H.-U. Moritz

Chapter 5. Movement and Hydrodynamic Instabilities of Particle-Laden Liquid Jets in the Centrifugal Field Influenced by a Gas Flow

In several industrial applications like spray drying or coating technologies, rotary atomizers are used for atomization of fluids. To control the fluid motion and to intensify transfer processes, rotary atomization is often combined with gas flows. The present work introduces experimental and theoretical studies on this issue. Model–theoretical basics and experiments were worked out for the breakup of a stretched, viscous, particle-laden, laminar liquid jet in the centrifugal field. In addition, the research takes into account the influence of an imposed gas flow which is directed parallel to the axis of rotation. Based on perturbation analysis, the physical–mathematical model consists of two parts. Balances of mass and forces provide the time steady flow and thus 3D jet motion and mean jet contour. Considering Rayleigh-type jet disintegration a linear stability analysis is used to examine the stability behavior of the jet. Spatial and temporal evolution of disturbances and finally median drop sizes are both calculated with a dispersion equation. The dispersion equation is based on a potential flow for the gas phase and on an Eulerian formulation for the balances of impulse and mass of the liquid and the solid phase. Experiments under various operating conditions and boundary conditions complete our investigations. Two shadow imaging systems provide projections from top and side. Therefore, three-dimensional jet motion is analyzable. Furthermore, jet length is determined and serves as a boundary condition for the modeling. Using a telecentric lens for the imaging from the side, drop sizes and jet thickness are measureable although jet and drops are moving three-dimensionally. Calculation results and experimental data are compared and show good accordance.
Thomas Kalmbach, Simon Gramlich, Manfred Piesche

Chapter 6. Experimental Investigation and Modeling of Coalescence and Agglomeration for Spray Drying of Solutions

Binary drop collisions were investigated with polymer solutions of a wide range of viscosities. Two experimental setups were constructed for producing droplet chains with liquids of low viscosities from 2 to 60 mPa · s and for liquids of high viscosities from 116 to 729 mPa · s. The low-viscous liquids were composed of three different aqueous solutions: sucrose with solids content from 20 to 60 %, PVP (1-Ethenyl-2-pyrrolidone) K17 with solids content from 5 to 35 %, and PVP K30 with solids content from 5 to 25 %. The high-viscous liquids were produced by PVP K17 solutions with solids content from 45 to 55 %. For the low-viscous liquids vibrating orifice drop generators were applied for drop generation, while for the high-viscous liquids a special drop generator based on pulse jetting was developed. Two drop trains were produced and the drops were directed toward each other at a certain angle so that individual droplet pairs collide with a desired velocity. For recording the collision events two high-speed cameras were used. One camera was positioned perpendicular to the collision plane recording the outcome of the collision, and the second camera was aligned parallel to the collision plane to assure that the droplet chains were exactly in one plane. Time-resolved series of pictures were used to analyze the dynamics of droplet collisions. Here, relative velocities between 0.5 and 4 m/s and impact parameters in the interval from 0 to 1 for equal-sized droplets have been investigated. For lower viscosities coalescence, reflexive separation, stretching separation, and bouncing were observed as outcomes of binary drop collisions. For this viscosity range, a model is proposed to predict the beginning of reflexive separation, using a viscosity-dependent correlation for the critical Weber number for head-on collisions. The existing model for stretching separation is found to be functional for a wide range of viscosities. The model constants could be uniquely related to the ratio of surface tension to dynamic viscosity for the different liquids considered. Thereby the shift of the triple point, where coalescence, bouncing and reflexive separation clustered together on the collision map, could be predicted. Experimental data for formation of satellite droplets were also provided. For the regime of high viscosities, the model for stretching separation was examined, and it is found that the model constants are dependent on the liquid viscosity. Additionally, collisions of droplets of different viscosities were investigated using the fluorescence technique. Penetration, or encapsulation, was documented, as well as delay of coalescence.
Hai Li, Matthias Kuschel, Martin Sommerfeld

Chapter 7. Particle Formation from Gas-Enriched Polymeric Melts and Polymeric Solutions

Within the scope of this subproject, a gas-assisted high-pressure spray process (PGSS—Particles from Gas-Saturated Solutions) was investigated. The gas used for the atomization is carbon dioxide (CO2) which for the most purposes is in supercritical state. In the spray process, the gas is partly dissolved into the liquid before the atomization. The dissolved CO2 changes the physical properties of the liquid such as viscosity and surface tension and enables high-viscous substances to be atomized. Several authors were able to atomize high-viscous substances such as polymers, fats, and waxes with such a spray process. Nevertheless, till now the fundamental influence of the CO2 on the atomization phenomena has not been taken into account. For this reason, experiments which shall clarify how the CO2 affects the spray and particle formation have been carried out systematically within this project. Sprays of water, polymers, and aqueous polymeric solutions were observed and investigated. The liquids were sprayed as pure substances as well as CO2-enriched substances from an autoclave in a batch wise working process. To get a deeper understanding of the observed effects, optically transparent spray geometries were developed. Observations of the flow regime of the gas-enriched liquids gave explanations of the governing atomization phenomena. The results of the experiments show that the working principle of the PGSS process is based on the phenomena of flash atomization. Classical phenomena such as jet and lamella breakup can be neglected for the continuously working process. In further experiments, powders of polyethyleneglycols (PEG 6000) were generated using the continuously working process. Several spray devices were used such as hollow cone nozzles, capillaries, and orifices. The results show that powders with average particle size distributions in the order of 100 μm can be generated independently from the design of the spray device. Therefore, it is proven, that the flash atomization is the governing working principle in the PGSS process.
In addition to the investigations of the spray phenomena, the effect of the CO2 on the solidification of droplets was observed. The temperature distributions in sprays gained from the batch wise process as well as from the continuously working process were compared. It was found that the cooling mainly results from the undissolved compressed gas. Compared to the amount of dissolved gas, the amount of undissolved gas is much higher. In the continuous process, there is a huge amount of undissolved gas. Therefore, in the continuous process, lower temperatures can be reached which enhance the solidification of the droplets.
Jan-Martin Loth, Sabine Kareth, Andreas Kilzer, Marcus Petermann

Chapter 8. A Real-Time Process Analysis System for the Simultaneous Acquisition of Spray Characteristics

In this paper, a Real-Time Process Analysis System for the characterization and measurement of spray and atomization processes is presented. Contrary to indirect measure methods such as phase Doppler interferometry (PDI) or laser diffraction, the proposed imaging system provides reliable measurement results for properties not only of (almost) spherical but also of arbitrarily shaped objects in spray and atomization processes. Compared to classical high-speed cameras which are based on the acquisition and storage of high-speed image sequences, the proposed Real-Time Process Analysis System evaluates a spray or atomization process for an arbitrary time period by processing each image frame in real time and transmitting the extracted measurement data to a PC. This allows the simultaneous measurement of a variety of spray properties. One example is the simultaneous measurement of the droplet or particle size and size distribution as well as the detection of pulsation and the pulsation frequency. Another example for the simultaneous detection of spray properties is the detection of droplet collisions and the measurement of the sizes of the colliding and collided droplets. Furthermore, filament formation or filament networks can be detected with the proposed system. Beyond the simultaneous measurement of various spray characteristics, the process analysis system computes all spray characteristics in real time so that these characteristics are immediately available in the experimental setup.
Michael J. Klaiber, Zhe Wang, Sven Simon

Process-Spray Meso Scale: Process Analysis, Modeling and Scaling


Chapter 9. Modeling and Simulation of Single Particle and Spray Drying of PVP- and Mannitol-Water in Hot Air

This contribution concerns the development of an integral model to describe spray drying processes, including droplet interactions, evaporation, and particle formation. Spray modeling requires the knowledge of single-droplet evaporation and drying, which constitutes the first part of this chapter, and then sprays are considered. Single-droplet drying in hot air below and above the boiling temperature is modeled, where the latter may lead to particle expansion and rupture and healing of the particle crust. For single droplets of mannitol and polyvinylpyrrolidone (PVP) solutions in water, the final particle characteristics are computed for different drying conditions such as the initial droplet diameter and initial solute mass fraction, and for the drying temperature and the air humidity. For mannitol-water droplets, the normalized surface reduction rate during the water evaporation appears to be mainly dependent on the initial droplet diameter and the drying temperature, whereas the final particle size depends on all studied parameters as well as on their correlations. Furthermore, an integral model for spray evaporation and interaction is presented. The spray process is modeled using Williams’ spray equation, which is solved with the direct quadrature method of moments (DQMOM). The spray and the gas strongly interact, and the equations for the liquid and the gas phase are coupled. The commonly used spray equation and the DQMOM formulation are extended to account for the variation of the droplet temperature. The numerical results with the new models are compared with the discrete droplet model (DDM) and with experimental data from G. Brenn, TU Graz, Austria. Both models show very good agreement with the experimental data, where the DQMOM method tops the DDM in terms of computational efficiency.
Holger Grosshans, Srikanth R. Gopireddy, Rana M. Humza, Eva Gutheil

Chapter 10. Droplet-Stream Freeze-Drying for the Production of Protein Formulations: From Simulation to Production

The objective of this interdisciplinary project was to develop a continuous atmospheric freeze-drying process for the production of lyophilized powder aerosols as pulmonary drug delivery systems in cooperation between an experimental and formulation group at the University of Bonn and a modelling and imaging team at the University of Halle (Saale). Observation and simulation results indicated deficiencies in the initial concept, which were eliminated by stepwise modifications of the freezing and drying system. Collisions and coalescence of droplets in fast streams exiting from piezoelectric generators were recorded by high-speed imaging and analyzed. Both the mean and the spread of the particle size distributions were reduced by a novel vortex-jet freezing technique. The fine particle fraction of the powder, which is suited to alveolar deposition in lungs, was increased to more than 40 %. In spite of the small size and low density of spherical and highly porous particles, the flowability of the powders is very good. Besides the powder aerosols envisaged in the initial concept, the method can be adapted to the production of other pharmaceutical dosage forms and may contribute to lowering the expenses and energy requirements for the manufacture of freeze-dried parenteral products.
The aim of the theoretical and numerical part of the project was the support of the technical realization of a continuous atmospheric spray-freeze-drying chamber using the Euler/Lagrange approach for numerically calculating the entire process and providing strategies for the design of the equipment and the optimal operational conditions. Since models for the drag coefficient of porous particles and the sublimation (drying) of frozen solution droplets are not available, a multi-scale approach was adopted. This implies that first the flow about a dry single porous particle and porous particles where the pore structure is fully filled with ice was proposed to simulate by the Lattice–Boltzmann method (LBM). Therefrom, appropriate correlations for drag and sublimation models shall be developed. Consequently, the available in-house LBM-code had to be extended by the calculation of the temperature field, fully coupled with the flow field. Moreover, a tracking model for the retraction of the ice structure inside the porous particle was proposed.
In parallel a sublimation model for Lagrangian calculations of the frozen particle phase was implemented. In the literature, two approaches for atmospheric freeze-drying have been developed: experimental diffusion models and the uniformly retreating ice front (URIF) model. In the experimental diffusion models, multi-component vapour diffusion mechanisms are reflected by experimentally determined effective diffusivity and activation energy. The URIF model is based on the assumption of equilibrium at the ice front interface and was selected for the present application. Simultaneous heat and mass transfer can be calculated solving the conservation equations of mass and energy. Preliminary calculations for the drying of single iced particles were conducted for validation.
Stefan Wanning, Markus Jäger, Sören N. Eggerstedt, Richard Süverkrüp, Alf Lamprecht, Matthias Dietzel, Matthias Kuschel, Ali Darvan, Martin Sommerfeld

Chapter 11. Correlations Between Suspension Formulation, Drying Parameters, Granule Structure, and Mechanical Properties of Spray Dried Ceramic Granules

Within this project, the correlations between internal structures of ceramic spray dried granules and resulting mechanical properties were investigated. A new method for the preparation and selective quantification of internal structure parameters based on image analysis was developed and evaluated within this project. On microstructure level the microporosity, particle distance or coordination number can be determined. The macrostructure can be characterized via shell thickness, batch composition or macroporosity determination.
The mechanical properties of spray dried granules can be modified in a defined way by adjusting shell thickness and/or microporosity: Increasing fracture strength can be achieved via increasing shell thickness or reducing microporosity. Comparisons of granule properties also showed increasing fracture deformation values via increase of shell thickness and/or increase of microporosity. For the investigated granules, a dominating influence of the microstructure (microporosity) was measured. Structural changes responsible for modified mechanical properties can be achieved via suspension formulation modification regarding solid content, particle size, or suspension temperature. Furthermore, spray drying parameters like drying temperature, atomizer type, or drying kinetics influence the structure formation and therewith mechanical properties if the added polyvinyl alcohol binder is kept constant.
If the additive content is modified, varied internal granule structures can be achieved, whereas the physical additive properties are decisive for the resulting mechanical granule properties.
Susanna Eckhard, Sören Höhn, Manfred Fries

Chapter 12. Statistical Extinction Method for the Inline Monitoring of Particle Processes

The object of this study is to develop a particle measurement system on the basis of the Statistical Extinction Method, which provides an inline monitoring of different particle processes. The Statistical Extinction Method determines from the mean value and root mean square deviation of a transmission signal through a particle collective, a mean particle size and a particle concentration. For the determination of particle size distribution, an advanced Statistical Extinction Method is developed and verified. This method requires the measurement of transmission signals of several light beams of different beam cross sections through a particle collective.
The validity of the Statistical Extinction Method is examined according to the derivation of its fundamental equations. The requirements on the metrological implementation of the method, as a result, are analyzed and evaluated. Since the method is influenced by some effects that are interacting with each other and difficult to examine, a simulation model for the extinction of light beams by particles is developed. With the simulation calculations, the effects can be examined separately and the quantitative correlation between the transmission signal and the effects influencing the signals can be discussed. Furthermore, the influence of the hardware-related measurement uncertainty on the Statistical Extinction Method is investigated by the simulation calculations. For a process-related applicability of the SE-Method, a number of optical sensor principles and concepts are formulated and developed on the basis of the derived requirements. These are verified with regard to their measurement capability. The validation of the method for different particle processes is carried out with suspensions, emulsions (Schwarz et al., Chemie Ingenieur Technik 86:1544, 2014), and spray processes at specifically designed test benches and sensor assemblies.
Florian Dannigkeit, Nico Schwarz, Siegfried Ripperger

Chapter 13. Numerical Simulation of Monodispersed Droplet Generation in Nozzles

The in-house developed open-source FEM-CFD software FeatFlow in the framework of the “SPP 1423 Prozess-Spray” project has been further extended with newly created modules exploiting state-of-the-art numerical techniques to provide a professional prediction tool being able to simulate the process of laminar jet breakup into single-phase or composite droplets. The two main “model” modules within the complete development are responsible for the dynamic Level Set-based interface capturing of the involved phases and for the non-Newtonian extension of the basic FeatFlow software which were successfully combined with an innovative performance improving ALE-based mesh deformation module. The developed modules have been successfully validated not only individually, but also in an interconnected fashion against experimental or computational reference data from inside as well as from outside of the SPP 1423 members. The long-term validation process involved the following test cases:
Rising of a gas bubble in a liquid environment
Laminar jet breakup in dripping and jetting mode
Coiling of laminar liquid jets in a gas environment
Oscillation of a non-Newtonian drop in a gas environment
The capability of the developed software covers the operation conditions of typical encapsulation processes, which from the application point of view defined the goal of our corresponding research. The developed software has been enriched with an additional module being responsible for the operational aspects of the droplet generation process by means of a flowrate modulation of the introduced dispersed phase(s). Thanks to the corresponding modulation mechanisms being also introduced into experimental setups in the form of periodic volumetric flowrate disturbances suggests an increased reproducibility of the numerical predictions with respect to experimental observations.
Otto Mierka, Stefan Turek

Chapter 14. Spray Drying Tailored Mannitol Carrier Particles for Dry Powder Inhalation with Differently Shaped Active Pharmaceutical Ingredients

Dry powder inhalation as commonly used in the local therapy of asthma or chronic obstructive pulmonary disease (COPD) is a very effective route of drug delivery. The system of small cohesive drug particles attached to the surface of large carriers with particle sizes >50 μm is successfully applied to numerous marketed products. The performance of these blends is based on the particle properties of both carriers and drug particles and is usually linked to the Fine Particle Fraction (FPF), which represents the fraction of drug particles with an aerodynamic diameter of 1–5 μm, which triggers the desired effect in the lung. Mannitol, which was chosen as an alternative carrier to the market-leading α-lactose monohydrate as it is highly crystalline in contrast to lactose even after spray drying, was prepared by spray drying to generate carrier particles at a range of 50–90 μm with various morphologies. This project was first aiming at the examination of the drying kinetics of bicomponent mannitol water droplets. It could be shown that high drying temperatures cause deep indentations and increasingly rough surface structures, while low drying temperatures result in spherical particles with rough surfaces at very low drying temperatures and smoother ones when increasing temperatures. Low rotation speeds and high mass fractions increase the particle size. Further particle properties like porosity, breaking strength or flowability were related accordingly. A defined set of mannitol batches was further selected for interactive powder blends with a micronised and spray dried quality of the model drug SBS. Particle–particle interactions were then investigated by correlating carrier properties to the resulting FPF. Particle shape was found to hinder the detachment of drug particles. Rough structures dried at the lowest drying temperatures were preferred for micronised drug particles, whereas spherical drug particles were preferably detached from smoother surfaces. This effect could be related to the drug size as only the detachment of the smallest drug particles (<1 μm) tended to be affected by the roughness. Carrier size was found to decrease the FPF for larger particles, when indentations occur simultaneously. Thus, it was possible to customise the carrier properties according to the drug particle properties to finally obtain adhesive drug–carrier mixtures with optimum aerodynamic performance.
Mathias Mönckedieck, Jens Kamplade, Eva Maria Littringer, Axel Mescher, Srikanth Gopireddy, Mats Hertel, Eva Gutheil, Peter Walzel, Nora Anne Urbanetz, Martin Köster, Hartwig Steckel, Regina Scherließ

Chapter 15. Pulverisation of Emulsions with Supercritical CO2

With the use of a carbon dioxide-assisted high pressure spraying process, it is possible to manufacture solid emulsions with or without the employment of surfactants. Depending on the process parameters, such as spray pressure, temperature, and gas-to-liquid ratio, various powder morphologies and sizes in the range of micrometers can be obtained. The aim of the project is to investigate and compare the fundamental differences in the spray formation mechanisms of this process to the conventional ones. To this end, firstly various high pressure thermo- and fluid dynamic data have been investigated to define the process and identify different effects coming from the liquid’s properties. Two model emulsions, water, and tristearin (water in oil) and rapeseed oil and polyethylene glycol (oil in water) have been chosen. Using a pseudo shadowgraphy technique spraying experiments with pure and gas-saturated liquids as well as the emulsions have been carried out with a flat fan orifice. The images of the sprays illustrate that the carbon dioxide generally leads to an earlier sheet breakup by gas nucleation. An increase in saturation pressure led to atomisation directly after the nozzle for rapeseed oil and tristearin. A decrease in breakup length of the liquid sheet was also observed for the water in oil emulsion. Solid emulsion particles were also produced in the range of 10 μm with various concentrations of the dispersed phase. It was shown that these can be produced without the use of an emulsifier. Moreover through the employment of an optical chamber, the encapsulation efficiency of the process was linked to the quality of the emulsion, that is size of dispersed droplets.
Pavlinka Ilieva, Andreas Kilzer, Eckhard Weidner

Chapter 16. Superheated Atomization

The project “Superheated atomization”, located at the Institute of Particle Technology (University of Erlangen-Nuremberg), focused on the characterization and evaluation of flash—or superheated—atomization. Flash atomization is based on a phase transition within or outside a nozzle, induced by a superheating prior to spraying. A multiphase flow can exists in the atomizer, containing bubbles with a higher inner pressure (corresponding to the vapor pressure of the sprayed fluid p v) than the ambient pressure p . These bubbles burst at the nozzle outlet, thereby disintegrating the fluid and generating a dispersed spray. Dependent on process conditions (e.g., fluid temperature T 0), nozzle geometry (e.g., L/D-ratio) and fluid material properties (e.g. shear viscosity η) different spray morphologies occur. Furthermore spray properties like the characteristic mean droplet size (Sauter mean diameter x 32) or spray temperature (T m) are influenced by the flow conditions inside the nozzle. In order to characterize the resulting spray, the flow behavior inside the nozzle has to be analyzed. Therefore, measurements like mass flux determination are conducted. For the general characterization of the superheated atomization, plain water is used. Furthermore, more complex media like polyvinylpyrrolidone solutions are sprayed and differences are monitored. The results are combined with measurement data of the spray itself, like droplet velocities, determined with Particle Image Velocimetry (PIV), allowing a dimensionless description of the whole atomization process. The superheated atomization enables the generation of a finely dispersed spray with a variety of atomizer geometries. Due to the fact that the shear viscosity is lowered with increasing fluid temperature, comparably fine droplets size distributions are formed, even for rather high subcooled shear viscosity values. In respect to particle formation, it its advantageous that 2–10 % of the fluid is evaporated as a side effect of the spraying process. Therefore, less liquid has to be removed in a downstream drying step for particle formation.
Astrid Günther, Karl-Ernst Wirth

Chapter 17. Direct Numerical Simulations of Shear-Thinning Liquid Jets and Droplets

Jets of non-Newtonian liquids are common in many technical applications from agriculture over food processing to medical applications. We use our in-house multiphase Computational Fluid Dynamics code Free Surface 3D (FS3D) to perform incompressible direct numerical simulations (DNS) of non-Newtonian liquid jets injected into air in the near nozzle region and single oscillating droplets. FS3D uses the Volume of Fluid (VOF) method for interface tracking in combination with piecewise linear interface calculation (PLIC) to reconstruct the liquid interface. DNS are uniquely suited to our investigations, as they let us simulate small-scale 3D phenomena like the deformation of a liquid surface or the breakup of ligaments into droplets, which coarser numerical methods are unable to simulate and experimental methods often have difficulties in capturing. Furthermore, they allow us to investigate information inside the liquids, such as the shear stress distribution.
Different aqueous solutions of shear-thinning fluids are numerically investigated. The Carreau–Yasuda model is introduced and fitted to experimental data to calculate the material properties of the solutions. We simulate different parameters which influence the stability of the jet such as the Reynolds number, the velocity profile of the injection representing different nozzle characteristics, ambient pressure, and the shear-thinning behavior of the liquid by varying the concentration of the solutions. We calculate the expansion of the jet and the increase in surface area from the simulation data and we analyze the viscosity inside the liquid jet. Furthermore, a quantitative analysis of the wave structures forming on the jet surface is performed in order to evaluate the influence of the different parameters. By this analysis, we make a step toward predicting the droplet size distributions resulting from the jet breakup.
We then simulate shape oscillations of shear-thinning droplets. At first the implementation of the Carreau–Yasuda model is validated against experimental data. We then analyze the droplet oscillations and compare them to Newtonian droplets with the same Ohnesorge number. We investigate the viscosity distribution inside the droplets and define an equivalent Ohnesorge number from the spatial average of the viscosity.
The results of our simulations and investigations provide on the one hand an insight into the influence of shear-thinning material properties on the primary breakup of liquid jets. On the other hand, we work toward the goal of providing information on droplet size distributions and droplet behavior which can then be used in large-scale simulations as well as for the better understanding of experimental measurements, thus providing ways to increase the efficiency of the above-mentioned processes.
Moritz Ertl, Bernhard Weigand

Chapter 18. Integral Process Modelling and Simulation for Solid-Particle-Forming Spray Processes

Solid particles are formulated in spray processes by atomization of a slurry or melt and successive solidification or drying of the droplets. The inter-correlations between the spray process conditions (atomizer types, raw material properties, operation conditions, etc.) and the powder product properties (particle size, morphology, structure, etc.) in spray processing of solid particles through integral process modelling and simulation are to be derived. A multiphase CFD-Continuum Model integrates different sub-process models dealing with various nozzle arrangements, liquid atomization, droplet spray, and particle consolidation phenomena. For quantitative descriptions of particle–droplet interactions in spray processes, particle–droplet collision model, and particle penetration model are developed based on numerical simulations. The integrative models are validated based on melt atomization process (two-phase) and spray process for composite-particle production (three-phase). The integral process model may be inverted to derive proper feed and process conditions for tailored particle production in a recursive design.
Xing-Gang Li, Sören Sander, Udo Fritsching

Process-Spray Macro Scale: Process Function, Particle and Powder Properties


Chapter 19. Hot Gas Atomization of Complex Liquids for Powder Production

The hot gas atomization technique is an integrated process where heated gas is used to atomize complex liquids. Simultaneously, the feed material is efficiently dried by the hot air to generate a powder. This technique is used to enhance the atomization of complex liquids and reduce the resulting fiber fraction in the final product. The characteristics of this integrated spray drying process are investigated by means of experiments and numerical simulation. The specific atomizer characteristics are studied by fragmenting polyvinylpyrrolidone (PVP)–water solutions with Newtonian and viscoelastic behavior. The feed materials’ rheological properties are investigated, for example, by filament stretching investigations to characterize the resistance towards elongation. Shadowgraphic images from the atomization process reveal the formation of filaments, similar to those in the single filament stretching experiments. The process is characterized by an intense contact of the hot gas with the dispersed phase. The drying rate close to the hot gas atomizer is high. The influence of the spray chamber design on the process characteristics (e.g., entrainment of gas and particle residence time) is analyzed to find potential improvements for this process.
The analysis of the influence of particle clustering on the heat and mass transfer within the spray has been investigated. Especially in the hot gas atomization process, the preferential concentration of particles is an important mechanism that increases the inhomogeneity in the spray. The cluster structures strongly depend on the local Stokes number and their formation is induced by coherent flow structures of the continuous gas phase.
Aljoscha Lampa, Udo Fritsching

Chapter 20. Polymerization in Sprays: Atomization and Product Design of Reactive Polymer Solutions

The focus of this novel process is to polymerize a water-based solution in a spray with a conventional spray dryer to produce powder polymers. To achieve a successful process design, this project aims at the atomization of water-based polymer solutions, a novel device to measure reactivity and the design of a pre-reaction nozzle. To overcome the short residence time in a spray dryer a pre-reaction is necessary. It is done within the nozzle, which can be described as a combination of a laminar pipe reactor with a variable length and a twin-fluid nozzle in a lance shape in order to place it easily in a spray dryer. A model to optimize the progress of polymerization within the nozzle is based on kinetics from literature and a viscosity approach. That is made with the help of the novel measurement and the theory of rheokinetics. The increase of viscosity is dependent on the progress of chain growing and the conversion, respectively. A power law is presented to describe the viscosity with changing conversion at a constant initiator ratio. Another important aspect of optimizing the pre-reaction is the influence of the viscosity on the atomization. Investigations show the strong dependency of the molecular weight of the polymer on the drop formation because of its influence on the rheology of the solution. Sprays of different polymer water mixtures are measured by laser diffraction and a two parameter model, RRSB, is successfully used to describe the drop size distribution. The influence of the Sauter mean diameter \( {\overline{x}}_{1;2} \) is only able to be discussed if it is calculated by the RRSB fit. With increasing mass fractions of the high molecular weight polymer a turning point from drop to ligament formation is shown at low shear viscosity compared to lower molecular weight polymers. Finally a laboratory plant is presented that is producing polymer powders in one, but complex, process.
Magnus Tewes, Urs Alexander Peuker

Chapter 21. Investigation on the Usage of Effervescent Atomization for Spraying and Spray Drying of Rheological Complex Food Liquids and on the Resulting Particle and Product Properties

The effervescent atomizer is an internal mixing pneumatic atomizer in which a two-phase flow prior to the nozzle orifice is created by adding gas in a mixing chamber. The resulting flow pattern is responsible for atomization of the liquid feed. In this study, two different single-phase and two multiphase model feeds were employed. Research was focused on the influence of the flow pattern inside the atomizer and the air-to-liquid ratio by mass (ALR) on the spray performance. The flow pattern inside the mixing chamber of the atomizer was recorded by high-speed cameras, while the one inside the nozzle orifice was determined by an optical sensor. Plug and annular flow was found in the mixing chamber, while a bubbly flow—reported for low viscous liquid feeds in literature—could not be formed due to the feed viscosity investigated in this study. The spray morphology investigations (shadowgraphy imaging and time-resolved spray drop size measurement) showed a clear connection of flow pattern and spray fluctuations. The latter are found for plug flow and have to be avoided for spray drying applications. Annular flow was found to be suitable for fine and stable spray characteristics and consequently atomizer geometry and ALR conditions for annular flow were determined. Moreover, the models of Lund and Geckler [J Fluids Eng 130:61303, 2008, Atomization Sprays, 3:77–89, 1993] were used to predict spray drop sizes. The comparison of these values to measured data gave additional insight in the spray mechanism. To investigate the influence of the atomization process on an inner phase of a multiphase feed, oil-in-water-emulsions were atomized and changes in the oil drop size were determined. Oil drop breakup and coalescence was found and could be described by classical emulsification theory. Finally, the investigated effervescent atomizers were used for spray drying experiments with single-phase feeds. The particle characteristics of the dried products were determined and showed a good agreement with the literature.
Agnes Kleinhans, Jewe Schröder, Philipp Stähle, Volker Gaukel, Heike P. Schuchmann

Chapter 22. Experimental Evaluation and Control of Interaction of Gas Environment and Rotary Atomized Spray for Production of Narrow Particle Size Distribution

The production of particles with a narrow particle size distribution by spray drying is a demanding challenge in industrial application. The laminar thread breakup is one option as employed by an innovative rotary spraying device (Schröder and Walzel, Chemical Engineering and Technology 21: 349–354, 1998; Erzeugung und Zerfall gedehnter Laminarstrahlen im Schwerefeld, Aachen, 2002; Designing thread forming rotary atomizers by similarity trials, 2012; Einfluss der Gasführung in Sprühtrocknern auf den Fadenzerfall an Rotationszerstäubern—Analyse und Optimierung, München, 2012). The feed enters the rotary wheel from the top and flows through the device as laminar open channel flow. It leaves the cup through bores and single laminar threads are obtained upon detachment. These threads ideally break up driven by surface tension. In spray experiments, a broader drop size distribution is observed than expected from theory. Within the presented work, the effect of a relative velocity between the thread the ambient gas on the laminar thread breakup is identified and addressed as mayor factor (Mescher et al., Chemical Engineering Science 69:181–192, 2012).
A similarity trial is used to quantify the influence of the cross-wind flow. The result influences the design of a gas distributor for small particles with a narrow size distribution. The gas distributor is designed by flow simulation (CFD) for noncommercial spray dryer (D = 2.7 m and H = 3.7 m) (Einfluss der Gasführung in Sprühtrocknern auf den Fadenzerfall an Rotationszerstäubern—Analyse und Optimierung, München, 2012). Spray drying experiments with aqueous PVP solution and Mannitol solution were performed to validate and to improve the gas distribution concept. Small particles with a narrow particle size distribution were obtained during experiments.
P. Walzel, A. Mescher, J. Kamplade

Chapter 23. Processing of Functional Capsule Powder Particles Based on Multiple Emulsions Using a Prilling Process

Present studies show the ability of cold spray processing (prilling) to tailor the morphology of simple or double emulsion-based fluid systems as investigated for two types of air-assisted nozzle geometries under various processing conditions. The spray process parameters varied were: (i) gas to liquid flow rate ratio (GLR), (ii) spraying pressure and (iii) total mass flow rate. The results depicted that the emulsion flow inside the nozzle (liquid cap) as well as in the spray (outside nozzle) have distinct impact on the resulting product structure due to the respective flow stresses acting. Increasing the flow stresses either lead to an additional dispersing impact or to separation and coalescence of the disperse fluid phase(s). Besides the process parameters, the material characteristics of the emulsion systems such as viscosity ratio λ of dispersed to continuous phase and the interfacial tension γ were varied in a wider range. The results demonstrated a systematic increase in structure stability for higher λ values within a range of 0.32–30. As representative dimensionless numbers, (a) a critical liquid Weber number We l,Drop,cr/λ and (b) a critical gas Weber number We g,Drop,cr/λ were defined to describe the effect of liquid cap-tip and air-assisted spraying, respectively, with respect to preserving the disperse microstructure of the treated emulsions. Above these critical We numbers, the dispersed emulsion phase drops were broken up and drop mean sizes were exponentially decreased due to the flow stresses acting either in the liquid flow inside the nozzle or in the spray filament outside the nozzle. Dynamic viscosity η and dynamic moduli (G′, G″) of treated emulsions increased with decreasing droplet size of the dispersed phase(s) thus altering the spraying performance as well as the properties of the liquid product systems reconstituted from resulting spray-chilled powders. A third critical Weber number We g,Nozzle,cr was derived for the spray droplet (tertiary droplet) generation by the spray filament breakup providing information of the smallest spray droplet that could be attained, while keeping the dispersed emulsion (secondary) droplets unchanged in size. The impact of We g,Nozzle on the resulting spray (tertiary) mean drop size was systematically explored for internal (INMIX) and external (EXMIX) liquid-gas mixing air-assisted nozzles. High-speed videography and laser shadowgraphy were applied to visualize liquid spray filament stretching and breakup, as well as the velocity distribution in the sprays. Sufficiently gentle spray conditions for complete preservation of the disperse emulsion structure were only achieved in the Rayleigh filament breakup regime.
Accordingly, a pressure controlled rotary “Rayleigh atomizer” was developed to study emulsion spraying by filament stretching and gently spray drop formation, preserving the emulsion (secondary) droplet structure. At the same time pressure adjustment enabled higher throughput rates compared to conventional rotary spraying nozzles for which only centrifugal forces determine filament stretch and throughput rate simultaneously. Filament length and drop size decreased with increasing rotational speed at a given total pressure (centrifugal pressure + static liquid pressure at the nozzle inlet) or flow rate, and the filament length and drop size increased with higher liquid pressures and related throughput rates at a given rotational speed. Chilling solidification of the spray drops was superimposed in selected cases. Prilling (spraying + chilling) was carried out for various emulsion systems in a prilling tower applying average air temperatures of ca. −10 °C for higher melting fat-continuous emulsions down to −50 °C for low melting oil- or water-continuous emulsions, in order to produce solid powder particles. The micro-structure of the solid particles was analyzed in further detail by cryo-scanning electron microscopy (Cryo-SEM). Concerning emulsion structure preservation in the sprayed products, the results clearly demonstrated that the disperse structure can differ significantly from the initial emulsion structure if critical flow stress conditions are exceeded. Respective process-structure functions were also quantified.
For emulsion-based prilled powders, the applicability and adjustability as functional component carriers for controlled release applications is of big interest in industries such as food, pharmaceutical and cosmetics. For related functional component release experiments we designed an in vitro gastric/duodenal setup. With this, the release kinetics of functional components encapsulated/embedded in dispersed secondary or primary emulsion drop phase(s) were quantified under simulated gastric or duodenal digestion conditions. Accordingly, an iron compound (micronutrient) was encapsulated into the primary and/or secondary dispersed emulsion droplets of simple or double emulsions, and related solid emulsion powder particles were produced through prilling applying our selected air-assist  atomizers. In a first testing step, the iron release kinetics for selected products were systematically investigated in the in vitro gastric system at pH ≈ 2.0, and quantified as a function of prill powder particle size, secondary emulsion drop size and prill powder storage time under ambient conditions.
Bipro Dubey, William Case, Erich J. Windhab

Chapter 24. Analysis of Mechanisms for PVP-Active-Agent Formulation as in Supercritical Antisolvent Spray Process

Supercritical antisolvent technology can precipitate polyvinylpyrrolidone (PVP) particles and crystallize paracetamol (PCM) crystals first separately and then together in the form of a solid dispersion. Supercritical carbon dioxide (scCO2) is used as an antisolvent. For PVP particle generation, ethanol, acetone, and mixtures of ethanol and acetone are used as solvents. The initial concentration of PVP in the solution was varied between 0.5 and 5 wt%, the operation pressure between 10 and 30 MPa, and the composition of ethanol/acetone solvent mixtures between 100 and 0 wt% of ethanol at a constant temperature of 313 K. An increase in the content of the “poor” solvent acetone in the initial solution leads to a significant decrease in mean particle size. Fully amorphous PVP powder always precipitates for all the parameters investigated.
For PCM powder generation, ethanol, acetone, and mixtures of ethanol and acetone are used as solvents. The initial PCM concentration in the solution was varied between 0.5 and 5 wt% and the operation pressure between 10 and 16 MPa. A variation of these parameters leads to a manipulation of the size and the morphology of the crystallized PCM crystals. Irrespective of parameters such as pressure or concentration, the same polymorphic form of paracetamol is always produced for pure solvents. When generating PCM particles from mixtures of ethanol and acetone, two different crystal forms were detected depending on the ratio between the solvents.
The solid dispersions were generated at different ratios of PVP to PCM. These solute mixtures were also dissolved in pure ethanol and pure acetone as well as in different mixtures of these two solvents. Fully amorphous solid dispersions consisting of PCM and PVP together were generated at different ratios of PVP to PCM. All influences of parameters were investigated and discussed in detail.
The mechanisms that control the final particle properties are discussed taking into account two different models for “ideal” and “nonideal” solutes. Furthermore, the study of “unconventional” supercritical antisolvent (SAS) process parameters such as the solvation power of the solvent shows that these parameters qualify to tailor polymer particle properties via SAS processing. In addition, investigating the behavior of both solutes separately, fully amorphous solid dispersions consisting of PCM and PVP together were generated. The crystalline structure and solid dispersions of the particles was analyzed using X-ray and their morphology was analyzed using scanning electron microscopy (SEM).
Matthias Rossmann, Daniel Bassing, Iolanda De Marco, Valentina Prosapio, Ernesto Reverchon, Eberhard Schlücker, Andreas Braeuer
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