Markus Thommes

Inline Determination of Residence Time Distribution in Hot-Melt-Extrusion

In the framework of Quality-by-Design (QbD), the inline determination of process parameters or quality attributes of a product using sufficient process analytical technology (PAT) is a center piece for the establishment of continuous processes as a standard pharmaceutical technology. In this context, Twin-Screw-Extrusion (TSE) processes, such as Hot-Melt-Extrusion (HME), are one key aspect of current research. The main benefit of this process technology is the combination of different unit operations. Several of these sub-processes are linked to the Residence Time Distribution (RTD) of the material within the apparatus. In this study a UV/Vis spectrophotometer from ColVisTec was tested regarding the suitability for the inline determination of the RTD of an HME process. Two different measuring positions within a co-rotating Twin-Screw-Extruder were compared to an offline HPLC–UV as reference method. The obtained results were overall in good agreement and therefore the inline UV/Vis spectrophotometer is suitable for the determination of the RTD in TSE. An influence of the measuring position on repeatability was found and has to be taken into consideration for the implementation of PATs. An effect of the required amount of marker on process rheology is not likely due to the low Limit-of-Quantification (LoQ).

Characterisation of fused deposition modeling 3D printers for pharmaceutical and medical applications

Abstract Fused deposition modeling (FDM) is a promising 3D printing technique for the fabrication of personalized drug dosage forms and patient-specific implants. However, there are no market products produced by FDM available at this time. One of the reasons is the lack of a consistent and harmonized approval procedure. In this study, three FDM printers have been characterised with respect to printing parameters relevant for pharmaceutical and medical applications, namely the positioning, hot-end temperature, material residence time, printing velocity and volumetric material flow. The printers are the Ultimaker 2 (UM2), the PRotos v3 (PR3) as well as an in-house developed printer (IDP). The positioning results showed discrepancies between the printers, which are mainly based on different types of drive systems. Due to comparable utilised hot-ends and nozzle geometries, the results for the temperature and residence time distribution measurements were quite similar. The IDP has a high positioning accuracy but is limited with respect to printing velocity, while the achievable material volume flows were different for all printers. The presented characterisation method aims to contribute to the development of a harmonized equipment qualification framework for FDM printers, which could lead to an acceleration and facilitation of an approval procedure for 3D printed products.

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.

Development of filaments for fused deposition modeling 3D printing with medical grade poly(lactic-co-glycolic acid) copolymers

Abstract The manufacturing of custom implants and patient-tailored drug dosage forms with fused deposition modeling (FDM) three-dimensional (3D) printing is currently considered to be very promising. Most FDM printers are designed as an open filament system, for which filaments with a defined size are required. In addition to this processing requirement, the filament material must be of medical or pharmaceutical quality, in order to be suitable in these applications. In this work, filaments with nominal diameters of 1.75 mm and diameter tolerances of ±0.05 mm or lower were developed in a continuous extrusion process. The filaments were made from different medical grade poly(lactic-co-glycolic acid) (PLGA) copolymers. Thermal characterization of the material with differential scanning calorimetry (DSC) showed increased material degradation with increasing hydrophilicity. Mechanical characterization of the filaments showed tensile strengths in the range of 41–48 MPa and Young’s moduli in the range of 2055–2099 MPa. Stress relaxation tests showed no irreversible change in filament diameter under processing conditions similar to the utilized 3D printer. Due to unexpected differences in processability in the 3D printer, the molecular weight of the materials was identified as an additional relevant parameter.

Preparation of spray dried submicron particles: Part A – Particle generation by aerosol conditioning

ABSTRACT The preparation of submicron‐sized particles is relevant in chemical, food and pharmaceutical applications. In pharmaceutics, spray dried submicron‐sized particles (0.1–1&mgr;m) can increase the dissolution rate as well as the solubility of poorly water‐soluble drugs. Since the particle size during spray drying is mainly influenced by the droplet size, the preparation of uniform droplets smaller than 3&mgr;m is of particular interest. In this work, a two‐fluid nozzle was combined with a cyclone droplet separator. Droplets larger than the cut‐off size were separated with a cyclone droplet separator and returned to the liquid feed. The aerosol at the outlet of the droplet separator was subsequently dried. The drop size of the conditioned aerosol was small, Symbol&mgr;m, and independent of the liquid‐to‐gas mass flow ratio and the viscosity of the liquid feed. Thus it only depended on the characteristics of the separator. Finally, the dried particles were spherical in shape and in the submicron‐sized range. Symbol. No caption available.

Preparation of spray dried submicron particles: Part B – Particle recovery by electrostatic precipitation

ABSTRACT The low bioavailability of poorly water‐soluble drugs is currently one of the major focuses of pharmaceutical research. One strategy currently being investigated to overcome this limitation is to decrease the particle size of the active pharmaceutical ingredients (API). An innovative process for this is spray drying with spray conditioning, which can produce submicron particles. One challenge resulting from this process is the recovery of these dispersed particles from a gas flow. Electrostatic precipitation is a common technique for air purification purposes, but an adapted electrostatic precipitator (ESP) design is necessary to achieve high collection efficiencies. The ESP design in this work uses the precipitation method of Penney filters which separates charging and collection into two stages. The ESP dimensions depend on various assumptions and simplifications. Several experiments were conducted to assess the performance of the ESP and characterize its behaviour in long‐term tests. The crucial parameters in the charging process are the residence time as well as the operating voltage. These constraints were examined to enhance the collection efficiency. Based on these tests it was possible to determine a suitable charging length as well as the dimensions of the collection stage. In conclusion, an ESP customized for collecting particles in the range of 0.1–1&mgr;m was designed, built and tested, and collection efficiencies higher than 99% were achieved for submicron particle size distributions. For a robust process continuous cleaning of the charging stage is necessary.

The Science and Practice of Extrusion-Spheronization

Extrusion-spheronization is one of the important techniques for pellet production. In most cases, the extruded-spheronized pellets are then coated with a functional coating. Extrusion-spheronization is a robust process and allows high drug loading of the pellets. The mean particle size is mainly determined by the die diameter, and its distribution is usually controlled to obtain a narrow particle size distribution. A pelletization aid is required to allow extrusion and spheronization of drugs, and microcrystalline cellulose (MCC) is the standard pelletization aid used in the industry. Different models have been used to explain the functionality of MCC. However, in certain cases MCC may not be suitable for this application, for example, in the case of drugs with low solubility, it may lead to slower drug release. In these cases, alternative pelletization aids like carrageenan or crospovidone have been studied. In recent years, the scale-down for early formulation development was in focus, and therefore, small-scale extruders and spheronizers have been developed. In case of twin-screw extruders, the feeding systems are of high importance with respect to constant product quality. The extrusion process control and application of process analytical technologies (PAT) have made significant progress. In addition, in recent years the spheronization process is better understood.

Spray Conditioning for the Preparation of Spray Dried Submicron Particles

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.