Verbesserung der Matrizenfüllung in der pharmazeutischen Tablettierung durch experimentelle und numerische Ansätze

Pharmaceutical tableting consists of three distinct stages: die filling, powder compaction, and tablet ejection. The first step is crucial with respect to the patient's safety as it defines the content and content uniformity of the active pharmaceutical ingredient(s). In this work, different experimental and numerical methods were developed to improve process understanding in die filling as in reality, nontransparent gravity or force feeders impede a detailed examination of the powder transfer into the dies. In the first step, a transparent model die filling system was developed to visualize powder discharge into the die by high speed camera imaging and to discern powder flow patterns. Several mathematical correlations were established to estimate the flowability for new materials in die filling and thus to quantify the effect of particle size enlargement on powder flowability improvement. The Discrete Element Method (DEM), which tracks each individual particle and thus provides a high level of detail in complex powder handling / transporting systems, was utilized to understand die filling in different gravity and force feeders. Thus powder flow patterns through the feeding systems could be discerned and the underlying size segregation mechanisms and dead / high shear zones identified. Those could be related to geometrical properties of the feeder types. First hints to critical material properties (powder cohesivity and particle-wall coefficient of friction) and critical process conditions (turret speed and paddle wheel speed) on critical quality attributes (tablet mass, tablet mass variation, and content uniformity) were provided. The application of different means, such as custom-designed instruments, statistical tools, and DEM, enabled a detailed understanding of powder flow in the tableting machine and its influence on tablet quality. Different levers for process and formulation optimization were presented and could aid pharmaceutical development in the context of the Quality by Design approach.Die Herstellung von Tabletten auf schnell-laufenden Rundläuferpressen kann in drei individuelle Schritte untergliedert werden: die Matrizenfüllung, die Pulverkompaktierung und den Tablettenausstoß. Die Matrizenfüllung sorgt für die Sicherheit des Patienten, da sie die Zusammensetzung und Gleichförmigkeit des Wirkstoffes vorgibt. In der vorliegenden Arbeit wurden experimentelle und numerische Methoden entwickelt, um diesen Prozessschritt besser zu verstehen, da die in der Realität undurchsichtigen Füllschuhgehäusematerialien verhindern, dass der Pulverfluss von außen beobachtet werden kann. Die Visualisierung des Matrizenfüllprozesses in einem transparenten Modell-System mittels einer Hochgeschwindigkeitskamera erlaubte die Identifizierung unterschiedlicher Fließmechanismen. Mathematische Zusammenhänge wurden entwickelt und dienen zur Abschätzung der Fließfähigkeit im Kontext des Matrizenfüllprozesses für neue Materialien und zur Quantifizierung des Einflusses der Partikelgrößenzunahme. In der Diskreten Element Methode (DEM), bei der jeder einzelne Partikel individuell betrachtet und, wurde verwendet, um den Pulvertransports im Kammer- und Rührflügelfüllschuh zu untersuchen. Die hohe Prozessauflösung durch die DEM erlaubte die Identifizierung von Segregationsmechanismen, Tot- und Scherzonen, die auf die geometrischen Eigenschaften der Füllschuhe zurückgeführt wurden. Der Einfluss potentiell kritischer Materialeigenschaften (Reibungskoeffizient Partikel-Geometrie und Kohäsion) und Prozessparametern (Tablettier- und Füllrädergeschwindigkeit) auf kritische Qualitätsmerkmale (Tablettengewicht, und -schwankung und Gleichförmigkeit des Gehalts) wurde aufgedeckt. Der Pulverfluss in der Tablettenpresse und dessen Einfluss auf die Tablettenqualität wurden mittels verschiedener Ansätze untersucht. Es wurden verschiedene Möglichkeiten zur Prozess- und Formulierungsoptimierung entwickelt, die die Entwicklung im Kontext des Quality by Design Ansatzes unterstützen können

Voltage-dependent structural changes of the membrane-bound anion channel hVDAC1 probed by SEIRA and electrochemical impedance spectroscopy

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.The voltage-dependent anion channel (VDAC) is a transmembrane protein that regulates the transfer of metabolites between the cytosol and the mitochondrium. Opening and partial closing of the channel is known to be driven by the transmembrane potential viaa mechanism that is not fully understood. In this work, we employed a spectroelectrochemical approach to probe the voltage-induced molecular structure changes of human VDAC1 (hVDAC1) embedded in a tethered bilayer lipid membrane on a nanostructured Au electrode. The model membrane consisted of a mixed self-assembled monolayer of 6-mercaptohexanol and (cholesterylpolyethylenoxy)thiol, followed by the deposition of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine vesicles including hVDAC1. The stepwise assembly of the model membrane and the incorporation of hVDAC1 were monitored by surface enhanced infrared absorption and electrochemical impedance spectroscopy. Difference spectra allowed for identifying the spectral changes which may be associated with the transition from the open to the “closed” states by shifting the potential above or below the transmembrane potential determined to beca.0.0 Vvs.the open circuit potential. These spectral changes were interpreted on the basis of the orientation- and distance-dependent IR enhancement and indicate alterations of the inclination angle of the β-strands as crucial molecular events, reflecting an expansion or contraction of the β-barrel pore. These protein structural changes that do not confirm nor exclude the reorientation of the α-helix are either directly induced by the electric field or a consequence of a potential-dependent repulsion or attraction of the bilayer.DFG, EXC 314, Unifying Concepts in CatalysisDFG, SFB 803, Funktionalität kontrolliert durch Organisation in und zwischen Membrane

An Intraoral OCT Probe to Enhanced Detection of Approximal Carious Lesions and Assessment of Restorations

Caries, the world’s most common chronic disease, remains a major cause of invasive restorative dental treatment. To take advantage of the diagnostic potential of optical coherence tomography (OCT) in contemporary dental prevention and treatment, an intraorally applicable spectral-domain OCT probe has been developed based on an OCT hand-held scanner equipped with a rigid 90°-optics endoscope. The probe was verified in vitro. In vivo, all tooth surfaces could be imaged with the OCT probe, except the vestibular surfaces of third molars and the proximal surface sections of molars within a 'blind spot' at a distance greater than 2.5 mm from the tooth surface. Proximal surfaces of 64 posterior teeth of four volunteers were assessed by intraoral OCT, visual-tactile inspection, bitewing radiography and fiber-optic transillumination. The agreement in detecting healthy and carious surfaces varied greatly between OCT and established methods (18.2–94.7%), whereby the established methods could always be supplemented by OCT. Direct and indirect composite and ceramic restorations with inherent imperfections and failures of the tooth-restoration bond were imaged and qualitatively evaluated. The intraoral OCT probe proved to be a powerful technological approach for the non-invasive imaging of healthy and carious hard tooth tissues and gingiva as well as tooth-colored restorations

Mapping local electric fields in proteins at biomimetic interfaces

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.We present a novel approach for determining the strength of the electric field experienced by proteins immobilised on membrane models. It is based on the vibrational Stark effect of a nitrile label introduced at different positions on engineered proteins and monitored by surface enhanced infrared absorption spectroscopy

The role of cell-free hemoglobin and haptoglobin in acute kidney injury in critically ill adults with ARDS and therapy with VV ECMO

Background: Increased plasma concentrations of circulating cell-free hemoglobin (CFH) are supposed to contribute to the multifactorial etiology of acute kidney injury (AKI) in critically ill patients while the CFH-scavenger haptoglobin might play a protective role. We evaluated the association of CFH and haptoglobin with AKI in patients with an acute respiratory distress syndrome (ARDS) requiring therapy with VV ECMO. Methods: Patients with CFH and haptoglobin measurements before initiation of ECMO therapy were identified from a cohort of 1044 ARDS patients and grouped into three CFH concentration groups using a risk stratification. The primary objective was to assess the association of CFH and haptoglobin with KDIGO stage 3 AKI. Further objectives included the identification of a target haptoglobin concentration to protect from CFH-associated AKI. Measurements and main results: Two hundred seventy-three patients fulfilled the inclusion criteria. Of those, 154 patients (56.4%) had AKI at ECMO initiation. The incidence of AKI increased stepwise with increasing concentrations of CFH reaching a plateau at 15 mg/dl. Compared to patients with low [= 15 mg/dl] CFH concentrations had a three- and five-fold increased risk for AKI (adjusted odds ratio [OR] moderate vs. low, 2.69 [95% CI, 1.25-5.95], P = 0.012; and OR high vs. low, 5.47 [2.00-15.9], P = 0.001). Among patients with increased CFH concentrations, haptoglobin plasma levels were lower in patients with AKI compared to patients without AKI. A haptoglobin concentration greater than 2.7 g/l in the moderate and 2.4 g/l in the high CFH group was identified as clinical cutoff value to protect from CFH-associated AKI (sensitivity 89.5% [95% CI, 83-96] and 90.2% [80-97], respectively). Conclusions: In critically ill patients with ARDS requiring therapy with VV ECMO, an increased plasma concentration of CFH was identified as independent risk factor for AKI. Among patients with increased CFH concentrations, higher plasma haptoglobin concentrations might protect from CFH-associated AKI and should be subject of future research

BIOHYBRID – Biohybrid templates for peripheral nerve regeneration

[Excerpt] Peripheral nerve injuries represent a major cause for morbidity and disability in affected patients and cause substantial costs for society in a global perspective. It has been estimated that peripheral nerve injuries affect 2.8% of trauma patients,many of whom acquire life-long disability (Noble et al., 1998). With respect to an incidence of nerve injuries of 13.9/100,000 inhabitants per year (Asplund et al., 2009) and the number of inhabitants in the EU (495,000,000 inhabitants in 2007), the number of peripheral nerve injuries requiring repair and reconstruction, excluding nerve injuries by amputations, may be 70,000 annually only in EU countries. Related to peripheral nerve injuries, the costs for society are substantial and consist of direct (costs for surgery, outpatient visits and rehabilitation) and indirect (lost production) costs. Individual median and ulnar nerve injuries in the forearm have total costs of EUR 51,000 and 31,000, respectively, where around 85% of the costs consist of loss of production (Rosberg et al., 2005), still excluding costs for adjusted quality of life ( Eriksson et al., 2011) . Thus, one may estimate that the annual costs only in the EU may be as high as EUR 2.2 billion, indicating that improved treatment strategies for peripheral nerve injuries may not only improve the situation for patients, but may also significantly reduce costs for society. [...](undefined

Allogeneic Non-Adherent Bone Marrow Cells Facilitate Hematopoietic Recovery but Do Not Lead to Allogeneic Engraftment

Background Non adherent bone marrow derived cells (NA-BMCs) have recently been described to give rise to multiple mesenchymal phenotypes and have an impact in tissue regeneration. Therefore, the effects of murine bone marrow derived NA-BMCs were investigated with regard to engraftment capacities in allogeneic and syngeneic stem cell transplantation using transgenic, human CD4+, murine CD4?/?, HLA-DR3+ mice. Methodology/Principal Findings Bone marrow cells were harvested from C57Bl/6 and Balb/c wild-type mice, expanded to NA-BMCs for 4 days and characterized by flow cytometry before transplantation in lethally irradiated recipient mice. Chimerism was detected using flow cytometry for MHC-I (H-2D[b], H-2K[d]), mu/huCD4, and huHLA-DR3). Culturing of bone marrow cells in a dexamethasone containing DMEM medium induced expansion of non adherent cells expressing CD11b, CD45, and CD90. Analysis of the CD45+ showed depletion of CD4+, CD8+, CD19+, and CD117+ cells. Expanded syngeneic and allogeneic NA-BMCs were transplanted into triple transgenic mice. Syngeneic NA-BMCs protected 83% of mice from death (n = 8, CD4+ donor chimerism of 5.8±2.4% [day 40], P<.001). Allogeneic NA-BMCs preserved 62.5% (n = 8) of mice from death without detectable hematopoietic donor chimerism. Transplantation of syngeneic bone marrow cells preserved 100%, transplantation of allogeneic bone marrow cells 33% of mice from death. Conclusions/Significance NA-BMCs triggered endogenous hematopoiesis and induced faster recovery compared to bone marrow controls. These findings may be of relevance in the refinement of strategies in the treatment of hematological malignancies