In-line UV-VIS spectroscopy in small scale extrusion as process analytical technology during early stage development of amorphous solid dispersions

The poor solubility of a large number of active pharmaceutical ingredients (API) 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 dissolve the API in an amorphous carrier polymer. During ASD development, crucial parameters as the dissolution and the decomposition 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 development and optimization based on in-line monitoring of crucial parameters using small amounts of material

Characterization and adsorption-based applications of nanoporous materials

The workshop program will focus on adsorption measurement techniques and methodologies for the assessment of adsorption properties and textural/structural characterization of novel nanoporous materials including zeolites, carbons, MOFs as well as materials consisting of hierarchically structured pore networks. A major point will be the correlation of textural properties, adsorption behavior, catalytic reaction pathways as well as transport properties with applications in gas and energy storage, separations and catalysis. Within this framework, the workshop will offer a platform for scientific discussions and for a knowledge transfer between various scientific areas where diffusion and transport properties of porous materials are of importance

Particle generation with liquid carbon dioxide emulsions

Spray drying is a common technique for particle generation. However, due to limitations in the droplet size, the production of solid submicron particles using conventional atomizers has proven to be challenging. With the aim of overcoming this limitation, the generation and expansion of emulsions of an aqueous solution and liquid carbon dioxide with a subsequent drying step was investigated. Potassium chloride concentrations in the solution between 0.1 and 10 wt. % and mass loads of the aqueous disperse phase between 0.01 and 0.09 were used in order to study their impact on the droplet and particle size. For the lowest potassium chloride concentration, median particle diameters in the submicron size range were measured for all mass loads of the disperse phase

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

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

Investigations concerning the residence time distribution of twin-screw-extrusion processes as indicator for inherent mixing

Over recent years Twin-Screw-Extrusion (TSE) has been established as a platform technology for pharmaceutical manufacturing. Compared to other continuous operation, one of the major benefits of this method is the combination of several unit operations within one apparatus. Several of these are linked to the Residence Time Distribution (RTD), which is typically expressed by the residence time density function. One relevant aspect for pharmaceutical processes is the mixing capacity, which is represented by the width of this distribution. In the frame of this study the influence of the mass flow, the temperature and the screw-barrel clearance were investigated for a constant barrel load (specific feed load, SFL). While the total mass flow as well as the external screw diameter affected the mixing performance, the barrel temperature had no influence for the investigated range. The determined results were additionally evaluated with respect to a fit to the Twin-Dispersion-Model (TDM). This model is based on the superimposition of two mixing functions. The correlations between varied process parameters and the obtained characteristic model parameters proved this general physical view on extrusion

Simulation of powder flow behavior in an artificial feed frame using an Euler‐Euler model

The Eulerian approach is an alternative numerical method to the traditionally used discreet particle techniques for modeling powder flow, avoiding limitations on particle number and diameter. The feasibility of an Euler-Euler simulation in a pharmaceutical application was investigated. In two- and three-dimensional flow simulations, computational fluid dynamics models and parameters were determined and verified based on comparison with experiments. Residence time distributions were calculated to show the applicability of the Eulerian model with two granular phases under the constraint of a continuous setup. Finally, this model was implemented to improve the process understanding of the powder flow in an artificial feed frame of a rotary tablet press

Spray Conditioning for the Preparation of Spray Dried Submicron Particles

[EN] Particle size reduction down to the submicron range (0.1-1 µm) is an effective option to increase the bioavailability of low water soluble active pharmaceutical ingredients. According to the Nernst-Brunner equation, the preparation of submicron sized particles increases the specific surface area, thus increases the dissolution rate. Conventional spray drying devices for submicron particles show certain limitations. The main challenge is the preparation of small and uniform droplets during the atomisation step. In this work, fine droplets were generated combining a nozzle with a droplet separator. Therefore, the aerosol is generated with a pneumatic nozzle and is sprayed into a cyclone droplet separator. Depending on the characteristics of the cyclone, droplets larger than the cut-off-size were separated and returned into the liquid feed. The conditioned aerosol at the top of the cyclone separator can then be introduced into the drying chamber. With this concept the usable part is separated, thus no classification process after drying is necessary. The investigations show that the dependencies during atomisation of the droplets size on the liquid-to-gas mass flow ratio µm and the liquid properties (e.g. viscosity) do not apply to the separation step. The conditioned aerosol only depends on the separation characteristics of the cyclone droplet separator. However, the amount of droplets separated is determined by the atomisation step. Hence, the amount of droplets smaller than the cut-off-size can be increased by decreasing the droplet size of the primary aerosol. This is realised by secondary droplet fragmentation. An impact surface causes breakup of the droplets of the primary aerosol before separation. The investigations show an increased amount of droplets <2µm.Gorny, R.; Schaldach, G.; Walzel, P.; Thommes, M. (2017). Spray Conditioning for the Preparation of Spray Dried Submicron Particles. En Ilass Europe. 28th european conference on Liquid Atomization and Spray Systems. Editorial Universitat Politècnica de València. 162-166. https://doi.org/10.4995/ILASS2017.2017.4701OCS16216

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