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The majority of tablets manufactured contain lubricants to reduce friction during ejection. However, especially for plastically deforming materials, e.g., microcrystalline cellulose (MCC), the internal addition of lubricants is known to reduce tablet tensile strength. This reduction is caused by the surface coverage by lubricant particles, the extent of which depends on both process and formulation parameters. Previously published models to predict the lubrication effect on mechanical strength do not account for changes in the excipient particle size. In this study, the impact of both lubricant concentration and mixing time on the tensile strength of tablets consisting of three different grades of MCC and four grades of magnesium stearate (MgSt) was evaluated. By taking into account the particle size of the applied excipients, a unifying relationship between the theoretically estimated surface coverage and compactibility reduction was identified. Evaluating the dispersion kinetics of MgSt as a function of time reveals a substantial impact of the initial surface coverage on the dispersion rate, while the minimal tensile strength was found to be comparable for the majority of formulations. In summary, the presented work extends the knowledge of lubricant dispersion and facilitates the reduction of necessary experiments during the development of new tablet formulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Tablets are commonly produced by internally adding particulate lubricants, which are known to possibly lower the mechanical strength of tablets. This reduction is caused by the coverage of matrix forming components by lubricant particles, resulting in decreased interparticulate interactions. The known incompatibilities with some active compounds of the predominantly used lubricant, magnesium stearate, call for the in-depth characterization of alternative lubricants., Purpose: Investigation of the dispersion behavior of five commonly applied pharmaceutical lubricants by mathematically modeling the dispersion kinetics for short and extended mixing times., Methods: The dispersion behavior of five different pharmaceutical lubricants were examined by systematically varying lubricant concentration and mixing time of binary formulations and evaluating the kinetic of tensile strength reduction by theoretically estimating the surface coverage based on particle sizes., Results: For short mixing times, a unifying relationship between compactibility reduction and theoretical surface coverage was identified. Subsequently, for extended mixing times, distinct differences in the shear strength and dispersion kinetics of the investigated lubricants were found., Conclusions: The lubricant particle size controls the tensile strength reduction if short mixing times are applied. For extended mixing times, the investigated lubricants can be divided into two groups in terms of dispersion kinetics. Possible underlying reasons are discussed in detail in order to enhance the general understanding of lubricant dispersions in tablet formulations., (© 2023. The Author(s).)

Probiotic microorganisms provide health benefits to the patient when administered in a viable form and in sufficient doses. To ensure this, dry dosage forms are preferred, with tablets in particular being favored due to several advantages. However, the microorganisms must first be dried as gently as possible. Here, the model organism Saccharomyces cerevisiae was dried by spray drying. Various additives were tested for their ability to improve yeast cell survival during drying. In addition, the influence of various process parameters such as inlet temperature, outlet temperature, spray rate, spray pressure and nozzle diameter was investigated. It was possible to dry the yeast cells in such a way that a substantial proportion of living microorganisms was recovered after reconstitution. Systematic variation of formulation and process parameters showed that the use of protective additives is essential and that the outlet temperature determines the survival rate. The subsequent compression of the spray-dried yeast reduced viability and survival could hardly be improved by the addition of excipients, but the tabletability of spray-dried yeast protectant particles was quite good. For the first time, loss of viability during compaction of spray-dried microorganisms was correlated with the specific densification, allowing a deeper understanding of the mechanism of cell inactivation during tableting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

As tablets are convenient to administer to patients, ensure safe dosing and allow cost-effective production on a large scale, they are the favored dosage form for numerous active pharmaceutical ingredients but also for the administration of viable probiotic microorganisms. Granules with viable yeast cells (Saccharomyces cerevisiae) formed by fluidized bed granulation with dicalcium phosphate (DCP), lactose (LAC) or microcrystalline cellulose (MCC) as carrier materials were tableted using a compaction simulator. Besides the compression stress, the compression speed was systematically studied by varying consolidation time and dwell time. The microbial survival as well as physical properties of the tablets, e.g., porosity and tensile strength, were determined. Higher compression stresses result in lower porosities. While on the one hand this has a detrimental effect on microbial survival (due to increased pressure and shear stress during particle rearrangement / densification), on the other hand it results in higher tensile strengths. At the same compression stress, a prolonged dwell time resulted in lower porosity and thus in lower survival rates but higher tensile strength. Against that, consolidation time showed no significant influence on the considered tablet quality attributes. Since changes of the tensile strength related survival rate were negligible (due to opposite but balancing dependence on porosity), high production speeds could be used for tableting of these granules without additional loss of viability, as long as tablets with the same tensile strength are produced., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tablets are the favored dosage form for numerous active pharmaceutical ingredients, among others because they are easy to take, ensure safe dosing and allow cost-effective production on a large scale. This dosage form is also frequently chosen for the administration of viable probiotic microorganisms. Saccharomyces cerevisiae cells granulated in a fluidized bed process, with dicalcium phosphate (DCP), lactose (LAC) and microcrystalline cellulose (MCC) as carrier materials, were tableted using a compaction simulator, varying the compression stress. The tablets were analyzed regarding physical properties, e.g., porosity and tensile strength, as well as microbial survival. Carrier material and compression stress showed a significant influence on survival rate and physical tablet properties. The dependencies were related to material specific deformation characteristics and linked to mechanistic approaches to explain the different sensitivities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Modeling of structural and mechanical tablet properties consisting of multiple components, based on a minimum of experimental data is of high interest, in order to minimize time- and cost-intensive experimental trials in the development of new tablet formulations. The majority of commonly available models use the compressibility and compactibility of constituent components and establish mixing rules between those components, in order to predict the tablet properties of formulations containing multiple components. However, their applicability is limited to single materials, which form intact tablets (e.g. lactose, cellulose) and therefore, they cannot be applied for lubricants. Lubricants are required in the majority of industrial tablet formulations and usually influence the mechanical strength of tablets. This study combines the multi-component compaction model of Reynolds et al. (2017) with a recently published lubrication model (Puckhaber et al. 2020) to describe the impact of multiple components on a formulation consisting of two diluents and a lubricant. By that, this model combination displays a meaningful extension of existing compaction models and allows the systematic prediction of properties of lubricated multi-component tablets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The purpose of this study was to investigate the deformation behavior of non-spherical particles during high-load compaction using the multi-contact discrete element method (MC-DEM). To account for non-spherical particles, the bonded multi-sphere method (BMS), which incorporates intragranular bonds between particles, and the conventional multi-sphere (CMS), where overlaps between particles are allowed to form a rigid body, were used. Several test cases were performed to justify the conclusions of this study. The bonded multi-sphere method was first employed to study the compression of a single rubber sphere. This method's ability to naturally handle large elastic deformations is demonstrated by its agreement with experimental data. This result was validated further through detailed finite element simulations (multiple particle finite element method (MPFEM)). Furthermore, the conventional multi-sphere (CMS) approach, in which overlaps between particles are allowed to form a rigid body, was used for the same objective, and revealed the limitations of this method in successfully capturing the compression behavior of a single rubber sphere. Finally, the uniaxial compaction of a microcrystalline cellulose-grade material, Avicel ® PH 200 (FMC BioPolymer, Philadelphia, PA, USA), subjected to high confining conditions was studied using the BMS method. A series of simulation results was obtained with realistic non-spherical particles and compared with the experimental data. For a system composed of non-spherical particles, the multi-contact DEM showed very good agreement with experimental data.

The administration of living microorganisms is of special interest, with regard to probiotic microorganisms providing health benefits to the patient. Effective dosage forms require the preservation of microbial viability until administration. Storage stability can be improved by drying, and the tablet is an especially attractive final solid dosage form due to its ease of administration and its good patient compliance. In this study, drying of the yeast Saccharomyces cerevisiae via fluidized bed spray granulation is investigated, as the probiotic Saccharomyces boulardii is a variety of it. Fluidized bed granulation enables faster drying than lyophilization on the one hand and lower temperatures than spray drying on the other hand, which are the two predominantly used techniques for life-sustaining drying of microorganisms. Yeast cell suspensions enriched with protective additives were sprayed onto the carrier particles of common tableting excipients, namely, dicalcium phosphate (DCP), lactose (LAC) and microcrystalline cellulose (MCC). Different protectants, such as mono-, di-, oligo- and polysaccharides, but also skimmed milk powder and one alditol, were tested; as they themselves, or chemically similar molecules, are known from other drying technologies to stabilize biological structures such as cell membranes, and thus, improve survival during dehydration. With the combined use of trehalose and skimmed milk powder, survival rates were 300 times higher than without the use of protective additives. In addition to these formulation aspects, the influence of process parameters such as inlet temperature and spray rate were considered. The granulated products were characterized regarding their particle size distribution, moisture content and the viability of the yeast cells. It has been shown that thermal stress on the microorganisms is especially critical, which can be reduced, for example, by reducing the inlet temperature or increasing the spray rate; however, formulation parameters such as cell concentration also influenced survival. The results were used to specify the influencing factors on the survival of microorganisms during fluidized bed granulation and to derive their linkages. Granules based on the three different carrier materials were tableted and the survival of the microorganisms was evaluated and linked to the tablet tensile strength achieved. Using LAC enabled the highest survival of the microorganisms throughout the considered process chain.

The poor bioavailability of many newly developed active pharmaceutical ingredients (APIs) poses a major challenge in formulation development. To overcome this issue, strategies such as the preparation of amorphous solid dispersions (ASDs), and the application of the APIs in lipid nanocarriers or the wet-milling of the substances into nanoparticles have been introduced. In addition to an efficient formulation strategy, a dosage form that is accepted by all patients is also of great importance. To enable a simple application of the oral dosage form for all patients, orodispersible films (ODFs) are a very promising delivery platform for the APIs because the films directly disintegrate in the mouth. In this study, two poorly water-soluble APIs, fenofibrate and naproxen, were formulated using five different formulation strategies and then embedded in ODFs. It was found that the deliverable amount of API with one ODF highly depends on the formulation strategy as well as the physicochemical properties of the formulated API. The most promising film formulations were ASD-ODFs as well as films with API-loaded lipid nanoemulsions. Both showed a reduction of the dissolution time of the APIs from the ODF compared to an ODF with unformulated API micro particles. In addition, short disintegration times were achieved, although the mechanical film properties were slightly worse compared to the API-free film formulation.

Promising active pharmaceutical ingredients (APIs) often exhibit poor aqueous solubility and thus a low bioavailability that substantially limits their pharmaceutical application. Hence, efficient formulations are required for an effective translation into highly efficient drug products. One strategy is the preservation of an amorphous state of the API within a carrier matrix, which leads to enhanced dissolution. In this work, mesoporous silica aerogels (SA) were utilized as a carrier matrix for the amorphization of the poorly water-soluble model drug ibuprofen. Loading of tailored SA was performed post-synthetically and solvent-free, either by co-milling or via the melting method. Thorough analyses of these processes demonstrated the influence of macrostructural changes during the drying and grinding process on the microstructural properties of the SA. Furthermore, interfacial SA-drug interaction properties were selectively tuned by attaching terminal hydrophilic amino- or hydrophobic methyl groups to the surface of the gel. We demonstrate that not only the chemical surface properties of the SA, but also formulation-related parameters, such as the carrier-to-drug ratio, as well as process-related parameters, such as the drug loading method, decisively influence the ibuprofen adsorption efficiency. In addition, the drug-loaded SA formulations exhibited a remarkable physical stability over a period of 6 months. Furthermore, the release behavior is shown to change considerably with different surface properties of the SA matrix. Hence, the reported results demonstrate that utilizing specifically processed and modified SA offers a compelling technique for enhancement of the bioavailability of poorly-water soluble APIs and a versatile adjustment of their release profile.

Various studies investigate the predictability of the compressibility and compactibility of tablet formulations based on the behaviour of the pure materials. However, these studies are limited to a few materials so far probably because of the complexity of the powder compaction process. One approach preventing the excessive increase in complexity is the extension of the investigations from pure materials to binary powder mixtures. The focus of this study is on the predictability of the compressibility and compactibility of binary mixtures consisting of an active pharmaceutical ingredient (API) and the excipient microcrystalline cellulose. Three APIs with markedly different deformation behaviour were used. The API concentration and type are systematically varied. For all three material combinations it is found that the in-die compressibility of the binary mixtures can be precisely predicted based on the characteristic compression parameters of the raw materials using the extended in-die compression function in combination with a volume-based linear mixing rule. Since the tablet porosity (out-of-die) also follows a linear mixing rule, the predictability can be further extended using the method of Katz et al. In contrast, the influence of the API concentration on compactibility or rather on tablet tensile strength is non-linear and strongly dependent on the deformation behaviour of the API, making the predictability more difficult. Neither the approach of Reynolds et al. nor this of Kuentz and Leuenberger are able to predict the compactibility when clear deviations from a linear mixing rule appear., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The production of nanosuspensions of poorly soluble active pharmaceutical ingredients (API) is a popular technique to counteract challenges regarding bioavailability of such active substances. A subsequent drying of the nanosuspensions is advantageous to improve the long-term stability and the further processing into solid oral dosage forms. However, associated drying operations are critical, especially with regard to nanoparticle growth, loss in redispersibility and associated compromised bioavailability. This work extends a previous study regarding the applicability of an API (itraconazole) nanosuspension as a granulation liquid in a fluidized bed process with focus on the influence of applied formulation parameters on the structure of obtained nanoparticle-loaded granules and their nanoparticle redispersibility. Generally, a higher dissolution rate of the carrier material (glass beads, lactose, mannitol or sucrose) and a higher content of a matrix former/hydrophilic polymer (PVP/VA or HPMC) in the granulation liquid resulted in the formation of coarser and more porous granules with improved nanoparticle redispersibility. HPMC was found to have advantages as a polymer compared with PVP/VA. In general, a better redispersibility of the nanoparticles from the granules could be associated with better dispersion of the API nanoparticles at the surface of the granules as deduced from the thickness of nanoparticle-loaded layers around the granules. The layer thickness on granules was assessed by means of confocal Raman microscopy. Finally, the dispersion of the nanoparticles in the granule layers was exemplarily described by calculation of theoretical mean nanoparticle distances in the granule layers and was correlated with data obtained from redispersibility studies.

On demand production of totally customizable combinative preparations is a central goal of a patient-centric pharmaceutical supply chain. Additive manufacturing techniques like fused deposition modeling (FDM) could be key technologies towards such individualized dosage forms. As so far only a limited number of studies on 3D printed combinative preparations applying FDM have been reported, a core-shell dosage form was the focus of the present study. Dosage forms with an initial and a sustained release part with theophylline as model API were successfully produced applying a dual nozzle FDM 3D printer. Investigations identified microstructural defects at the interface between the two formulations by means of µCT analysis. Dissolution testing proved the achievement of the intended release profile. In combination with additionally characterized release profile of single material prints of different shapes, the combinative release profiles could be predicted by developing model equations and taking into account the geometric composition. As these model approaches can accordingly facilitate the prediction of API release from 3D printed combinative preparations with only data from single material release. This is a first step towards a truly individualized and reliable patient-centric pharmaceutical supply via 3D printing., (Copyright © 2022. Published by Elsevier B.V.)

The tableting of most pharmaceutical formulations requires the addition of lubricants to reduce ejection forces, prevent tooling damage and tablet defects. The internal addition of lubricants is known to reduce tablet tensile strength, especially of mainly plastically deforming materials. To date, available models show only limited quantitative predictive accuracy for the influence of lubricant concentration on the mechanical strength of tablets. This study aims to fill this gap and present a model based on the Ryshkewitch-Duckworth equation that can estimate the compactibility profiles of lubricated formulations. Binary mixtures of different diluents (microcrystalline cellulose and lactose) were prepared with common lubricants (magnesium stearate and sodium stearyl fumarate) and subsequently tableted. The resulting compactibility profiles were fitted using the Ryshkewitch-Duckworth equation and the derived fit parameters (k b and σ 0 ) were correlated with the lubricant concentration. Subsequently, an empirical model was established which requires a minimum of experimental data and is able to predict the tensile strength of lubricated diluent tablets. Consequently, the developed empirical model is an interesting and valuable addition to the existing multi-component compacting models available and offers the opportunity to accelerate experimentation in the development of new tablet formulations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Study of human monocytic Myeloid-Derived Suppressor cells Mo-MDSC (CD14 + HLA-DR neg/low ) has been hampered by the lack of positive cell-surface markers. In order to identify positive markers for Mo-MDSC, we performed microarray analysis comparing Mo-MDSC cells from healthy subjects versus CD14 + HLA-DR high monocytes. We have identified the surface ectoenzyme Vanin-2(VNN2) protein as a novel biomarker highly-enriched in healthy subjects Mo-MDSC. Indeed, healthy subjects Mo-MDSC cells expressed 68 % VNN2, whereas only 9% VNN2 expression was observed on CD14 + HLA-DR high cells (n = 4 p < 0.01). The top 10 percent positive VNN2 monocytes expressed CD33 and CD11b while being negative for HLA-DR, CD3, CD15, CD19 and CD56, consistent with a Mo-MDSC phenotype. CD14 + VNN2 high monocytes were able to inhibit CD8 T cell proliferation comparably to traditional Mo-MDSC at 51 % and 48 % respectively. However, VNN2 expression on CD14 + monocytes from glioma patients was inversely correlated to their grade. CD14 + VNN2 high monocytes thus appear to mark a monocytic population similar to Mo-MDSC only in healthy subjects, which may be useful for tumor diagnoses., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due to the frequent occurrence of high hydrodynamic forces, among other reasons. In this study, 3D tomographic laser-induced fluorescence imaging (3D Tomo-LIF) is applied to analyse tablet disintegration and dispersion. Disintegration time (DT) and time-resolved particle size distribution in close proximity to the tablet are determined in a continuously operated flow channel, adjustable to very low fluid velocities. A case study on tablets of different porosity, which are composed of pharmaceutical polymers labelled with a fluorescent dye, a filler, and disintegrants, is presented to demonstrate the functionality and precision of the novel method. DT results from 3D Tomo-LIF are compared with results from the SDT, confirming the analytical limitations of the pharmacopoeial disintegration test. Results from the 3D Tomo-LIF method proved a strong impact of fluid velocity on disintegration and dispersion. Generally, shorter DTs were determined when cross-linked sodium carboxymethly cellulose (NaCMCXL) was used as disintegrant compared to polyvinyl polypyrrolidone (PVPP). Tablets containing Kollidon VA64 were found to disintegrate by surface erosion. The novel method provides an in-depth understanding of the functional behaviour of the tablet material, composition and structural properties under in vivo-like hydrodynamic forces regarding disintegration and the temporal progress of dispersion. We consider the 3D Tomo-LIF in vitro method to be of improved biorelevance in terms of hydrodynamic conditions in the human stomach.

The purpose of this work is to simulate the powder compaction of pharmaceutical materials at the microscopic scale in order to better understand the interplay of mechanical forces between particles, and to predict their compression profiles by controlling the microstructure. For this task, the new framework of multi-contact discrete element method (MC-DEM) was applied. In contrast to the conventional discrete element method (DEM), MC-DEM interactions between multiple contacts on the same particle are now explicitly taken into account. A new adhesive elastic-plastic multi-contact model invoking neighboring contact interaction was introduced and implemented. The uniaxial compaction of two microcrystalline cellulose grades (Avicel ® PH 200 (FMC BioPolymer, Philadelphia, PA, USA) and Pharmacel ® 102 (DFE Pharma, Nörten-Hardenberg, Germany) subjected to high confining conditions was studied. The objectives of these simulations were: (1) to investigate the micromechanical behavior; (2) to predict the macroscopic behavior; and (3) to develop a methodology for the calibration of the model parameters needed for the MC-DEM simulations. A two-stage calibration strategy was followed: first, the model parameters were directly measured at the micro-scale (particle level) and second, a meso-scale calibration was established between MC-DEM parameters and compression profiles of the pharmaceutical powders. The new MC-DEM framework could capture the main compressibility characteristics of pharmaceutical materials and could successfully provide predictions on compression profiles at high relative densities.

The functional behaviour of tablets is strongly influenced by their manufacturing process and the choice of excipients. Water uptake and swelling are prerequisites for tablet disintegration, dispersion and hence active pharmaceutical ingredient (API) dissolution. High proportions of polymeric excipients in tablets, which are typically used as API carriers in amorphous solid dispersions (ASDs), may be challenging due to the formation of a gelling polymer network (GPN). In this study, systematic investigations into the formulation development of tablets containing polymeric and other excipients are performed by water uptake and swelling analysis. The impact of tablet composition and porosity as well as pH of the test medium are investigated. The pH affects the analysis results for Eudragit L100-55 and Eudragit EPO. HPMC and Kollidon VA64 inhibit water uptake and swelling of tablets due to the formation of a GPN. High tablet porosity, coarse particle size of the polymer and the addition of fillers and disintegrants can reduce the negative impact of a GPN on tablet performance. The application of lubricants slows down the analysed processes. Water uptake and swelling data are fitted to an empirical model obtaining four characteristic parameters to facilitate the simple quantitative assessment of varying tablet formulations and structural properties., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Applying additives and excipients during the dry processing of fine particles is a common measure to control the particle-particle interactions, to specifically influence the powder properties and to enhance the process efficiency or product quality. In this study, the impacts of a particulate lubricant, a nano-disperse flow additive and liquid grinding aids on the dry fine milling and subsequent tableting of the ground material were investigated for three different organic model compounds. It is presented that the three additive classes cause varying and partly opposing effects during these process steps. Especially the lubricant and the grinding aids were shown to increase the efficiency of the milling process as well as the product fineness of the ground material, and to avoid critical product adhesions on the machine surfaces. Thereby, stable and efficient grinding conditions were partially not possible without the addition of such additives. However, as these positive effects are attributed to a reduction of the adhesive forces between the particles, much lower tablet strengths were achieved for these additives. This propagation of powder, and in turn, final product properties over whole process chains, has not been studied in detail so far. It was further revealed that the material behavior and the microstructure of the product particles is decisive for the processing as well, which is why additive effects may be product-specific and can even be suppressed under certain processing conditions. In comparison to the process performances, the powder properties and surface energies of the product particles were less influenced by the additives. On the contrary, particle-based morphologies or deformation behavior seem to play a major role in comparison to inorganic materials. Thus, it can be stated that global bulk properties and surface energies provide first indications of powder behavior and susceptibility. However, additional specific properties need to be evaluated to more clearly understand the influences of additives.

The deformation behaviour of a powder and, thus, of the individual particles is a crucial parameter in powder compaction and affects powder compressibility and compactibility. The classical approach for the characterization of the deformation behaviour is the performance of powder compression experiments combined with the application of mathematical models, such as the Heckel-Model, for the derivation of characteristic compression parameters. However, the correlation of these parameters with the deformation behaviour is physically often not well understood. Single particle compression and nanoindentation enables the in-depth investigation of the deformation behaviour of particulate materials. In this study, single particle compression experiments were performed for the characterization of the deformation behaviour of common pharmaceutical excipients and active pharmaceutical ingredients (APIs) with various, irregular particle morphologies of industrial relevance and the findings are compared with the results from powder compression. The technique was found useful for the characterization and clarification of the qualitative deformation behaviour. However, the derivation of a quantitative functional relationship between single particle deformation behavior and powder compression is limited. Nanoindentation was performed as complementary technique for the characterization of the micromechanical behavior of the APIs. A linear relationship between median indentation hardness and material densification strength as characteristic parameter derived by in-die powder compression analysis is found., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Within this study, tablets microstructure was investigated by X-ray microtomgraphy. The aim was to gain information about their microstructure, and thus, derive deeper interpretation of tablet properties (mechanical strength, component distribution) and qualified property functions. Challenges in image processing are discussed for the correct identification of solids and voids. Furthermore, XMT measurements are critically compared with complementary physical methods for characterizing active pharmaceutical ingredient (API) content and porosity and its distribution (mercury porosimetry, calculated tablet porosity, Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM)). The derived porosity by XMT is generally lower than the calculated porosity based on geometrical data due to the resolution of the XMT in relation to the pore sizes in tablets. With rising compactions stress and API concentration, deviations between the actual and the calculated API decrease. XMT showed that API clusters are present for all tablets containing >1 wt% of ibuprofen. The 3D orientation of the components is assessable by deriving cord lengths along all dimensions of the tablets. An increasing compaction stress leads to rising cord lengths, showing higher connectivity of the respective material. Its lesser extent in the z-direction illustrates the anisotropy of the compaction process. Additionally, cracks in the fabric are identified in tablets without visible macroscopic damage. Finally, the application of XMT provides valuable structural insights if its limitations are taken into account and its strengths are fostered by advanced pre- and post-processing., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

In pharmaceutical manufacturing, the utmost aim is reliably producing high quality products. Simulation approaches allow virtual experiments of processes in the planning phase and the implementation of digital twins in operation. The industrial processing of active pharmaceutical ingredients (APIs) into tablets requires the combination of discrete and continuous sub-processes with complex interdependencies regarding the material structures and characteristics. The API and excipients are mixed, granulated if required, and subsequently tableted. Thereby, the structure as well as the properties of the intermediate and final product are influenced by the raw materials, the parametrized processes and environmental conditions, which are subject to certain fluctuations. In this study, for the first time, an agent-based simulation model is presented, which enables the prediction, tracking, and tracing of resulting structures and properties of the intermediates of an industrial tableting process. Therefore, the methodology for the identification and development of product and process agents in an agent-based simulation is shown. Implemented physical models describe the impact of process parameters on material structures. The tablet production with a pilot scale rotary press is experimentally characterized to provide calibration and validation data. Finally, the simulation results, predicting the final structures, are compared to the experimental data.

The physical characteristics of raw materials determine powder compression and compaction performance as relevant in pharmaceutical processes. For instance, the influence of initial particle size on powder compression and the resulting strength of specimen are highly complex and are still not sufficiently understood. Existing studies are often limited to materials with well-defined deformation behaviour, such as purely brittle or ductile. However, the deformation behaviour of active pharmaceutical ingredients (APIs) is often more complex. In this study, the influence of initial particle size on powder compressibility and compactibility is systematically characterized by consideration of in-die compressibility, specific energies, quick elastic recovery, tablet porosity and, tensile strength for the binder microcrystalline cellulose and three APIs. The decrease of particle size leads to an increase of the resistance against compression by trend and probably to a different contribution of the acting deformation mechanisms. The compactibility is increased with decreasing particle size because of the increasing number of bonds in a cross-sectional area of the tablet, as found by the application of the model of Rumpf. Furthermore, it is found that the model of Rumpf combined with the JKR model provides a meaningful property function to estimate tablet tensile strength., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Renal cell carcinoma (RCC) is the most common type of kidney cancer and comprises several subtypes with unique characteristics. The most common subtype (~70% of cases) is clear-cell RCC. RCC is considered to be an immunogenic tumour but is known to mediate immune dysfunction in large part by eliciting the infiltration of immune-inhibitory cells, such as regulatory T cells and myeloid-derived suppressor cells, into the tumour microenvironment. Several possible mechanisms have been proposed to explain how these multiple tumour-infiltrating cell types block the development of an effective anti-tumour immune response, including inhibition of the activity of effector T cells and of antigen presenting cells via upregulation of suppressive factors such as checkpoint molecules. Targeting immune suppression using checkpoint inhibition has resulted in clinical responses in some patients with RCC and combinatorial approaches involving checkpoint blockade are now standard of care in patients with advanced RCC. However, a substantial proportion of patients do not benefit from checkpoint blockade. The identification of reliable biomarkers of response to checkpoint blockade is crucial to facilitate improvements in the clinical efficacy of these therapies. In addition, there is a need for the development of other immune-based strategies that address the shortcomings of checkpoint blockade, such as adoptive cell therapies.

Background: Myeloid-derived suppressor cells (MDSC) have immunosuppressive activity and enhance tumor progression. We hypothesized that lower blood MDSC would correlate with pathologic complete response and better outcomes in nonmetastatic urothelial carcinoma (UC)., Patients and Methods: Before cystectomy, blood MDSC were measured in whole blood (WB) and peripheral blood mononuclear cells using flow cytometry. MDSC were defined as CD33 + /HLA-DR - . MDSC subtypes were polymorphonuclear MDSC (CD15 + /CD14 - ), monocytic (M)-MDSC (CD15 - /CD14 + ), and uncommitted (UnC) MDSC (CD15 - /CD14 - ). The Wilcoxon rank sum test was used to compare MDSC between pathologic complete response groups. The optimal cutoff points for MDSC were identified using recursive partitioning analysis with cross-validation. The Cox proportional hazard model was used to associate MDSC and other clinical factors with recurrence-free survival and overall survival (OS)., Results: Overall, 109 patients were included: 86% men with median (range) age of 67 (30-88) years, 76% with pure UC, 29% intravesical therapy, and 41% neoadjuvant chemotherapy. Twenty-one patients (19%) had pT0N0 and 23 (24%) < pT2N0. Median (range) follow-up time was 17.4 (0.4-42.4) months. Total MDSC and polymorphonuclear MDSC percentage in peripheral blood mononuclear cells was significantly lower in patients with pT0N0 disease (P = .03). One- and 2-year OS rates were 94% (95% confidence interval [CI], 90-99) and 83% (95% CI, 75-93), respectively. In the multivariate Cox model after adjusting for age and gender, patients with higher WB M-MDSC and UnC-MDSC had shorter OS (optimal cutoff points by recursive partitioning analysis, hazard ratio = 7.5 [95% CI, 2.5-22.8], P = .0004; hazard ratio = 3.4 [95% CI, 1.0-11.0], P = .046, respectively)., Conclusion: In patients with nonmetastatic UC of bladder, higher WB M-MDSC and UnC-MDSC before cystectomy had negative prognostic value. Prospective validation is warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Active pharmaceutical ingredient (API) nanosuspensions from naproxen (Nap) and itraconazole (Itra) stabilized with Kollidon®VA64 (KVA) and sodium dodecyl sulfate (SDS) were produced in two different size classes each by wet media milling. These API nanosuspensions were spray dried with lactose, trehalose and sucrose as matrix formers in different proportions and at different drying temperatures (T outlet ). T outlet as well as the API content significantly influenced the redispersibility of the API nanoparticles. It could be shown that these two parameters are related to each other, with an increasing API content leading to a decreasing maximum applicable T outlet (T critical ). Drying above T critical always led to an alteration of the size characteristics of the API nanoparticles and thus to a non-redispersible product with respect to the defined quality criteria. For each proportion of API to matrix former, a T critical could be found. T critical showed a linear relation to the API content. The linear regression of this relation was defined as process boundary. The y-intercept of the process boundary correlated well with the glass transition temperature (T g ) of the pure matrix former used for spray drying. The two APIs under investigation led to virtually identical behaviour if other parameters were kept constant. The particle size of the initial nanosuspension had an important influence. Nanosuspensions with comparatively small particle sizes led to a significantly stronger decrease of the process boundaries compared to the use of larger particle sizes. The maximum API content that leads to a redispersible product is thus decisively determined by Toulet of the spray dryer, T g as well as the proportion of the matrix former and by the particle size of the API nanoparticles used., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The particle size reduction of active pharmaceutical ingredients is an efficient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient's convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the influence of several formulation parameters (i.e., type of carrier material, type and amount of additional polymeric drying excipient in the nanosuspension) on the redispersibility of naproxen nanoparticle-loaded granules produced in a fluidized bed process was investigated. The dissolution rate of the carrier material (i.e., sucrose, mannitol, or lactose) was identified as a relevant material property, with higher dissolution rates (sucrose > mannitol > lactose) resulting in better redispersibility of the products. Additionally, the redispersibility of the product granules was observed to improve with increasing amounts of polymeric drying excipient in the nanosuspension. The redispersibility was observed to qualitatively correlate with the degree of nanoparticle embedding on the surface of the corresponding granules. This embedding was assumed to be either caused by a partial dissolution and subsequent resolidification of the carrier surface dependent on the dissolution rate of the carrier material or by resolidification of the dissolved polymeric drying excipient upon drying. As the correlation between the redispersibility and the morphology of the corresponding granules was observed for all investigated formulation parameters, it may be assumed that the redispersibility of the nanoparticles is determined by their distance in the dried state.

Background: Myeloid-derived suppressor cells (MDSCs) were linked to pathologic stage in bladder urothelial carcinoma (UC). Neutrophil lymphocyte ratio (NLR) is an inflammatory biomarker with a prognostic role in metastatic (m)UC., Objective: We hypothesized that MDSC levels correlate with NLR and overall survival (OS) in mUC., Patients and Methods: MDSCs were measured in blood samples from patients with mUC in fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC) by flow cytometry and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UNC-MDSC: CD15-/CD14-). MDSC populations were presented as a percentage of live nucleated blood cells. Spearman's rank correlation assessed correlations between MDSC and NLR. Kaplan-Meier curves and log-rank test estimated OS from the time of MDSC collection to last follow-up or date of death., Results: Of the 76 patients, 78% were men and 43% were never smokers with a median age of 69 years (range 31-83); 72% had pure UC and 76% had lower tract UC. Prior therapies included intravesical therapy (22%), neoadjuvant chemotherapy (30%), cystectomy or nephroureterectomy (55%). Median follow-up for all patients was 12 months (0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p ≤ 0.001). Both WB UNC-MDSC/PMN-MDSC ratios (rho = - 0.27, p = 0.03) and PBMC UNC-MDSC/PMN-MDSC (rho = - 0.28, p = 0.02) were negatively correlated with NLR. Median OS was 17.7 months (95% CI: 11.0-NE). Overall 1-year and 3-year survival rates were 0.60 (95% CI 0.49-0.73) and 0.15 (95% CI 0.03-0.67), respectively. Higher WB UNC-MDSC levels (HR 3.78, p = 0.0022) and higher NLR (HR 2.6, p = 0.0179) were associated with shorter OS., Conclusions: Specific MDSC subsets correlate with NLR. Higher WB UNC-MDSC levels and higher NLR were negative prognostic factors. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow-up are warranted.

Compaction simulators are frequently used in the formulation and process development of tablets, bringing about the advantages of flexibility, low material consumption, and high instrumentation to generate the most possible process understanding. However, their capability of resembling general aspects of rotary press compaction and their precision in simulating or mimicking sub-processes such as feeding and filling need to be systematically studied. The effect of material deformation behavior, blend composition, and feeding on tensile strength and simulation precision as compared with rotary presses of different scales is evaluated in this study. Generally, good simulation performance was found for the studied compaction simulator. Compaction profile-sensitivity was demonstrated for highly visco-plastic materials while shear-sensitivity in feeding was demonstrated for lubricated blends of ductile particles. Strategies for the compensation of both in compaction simulator experiments are presented by careful investigation of the compaction stress over time profiles and introduction of a compaction simulator-adapted shear number approach to account for differences in layout and operation mode between compaction simulator and rotary press, respectively. These approaches support the general aim of this study to provide a more straightforward determination of scaling process parameters between rotary press and compaction simulator and facilitate a quicker and more reliable process transfer.

Paddle feeders are devices commonly used in rotary tablet presses to facilitate constant and efficient die filling. Adversely, the shear stress applied by the rotating paddles is known to affect the bulk properties of the processed powder dependent on the residence time. This study focuses on the residence time distribution (RTD) of two commonly applied excipients (microcrystalline cellulose, MCC; dicalcium phosphate, DCP), which exhibit different flow properties inside rotary tablet presses. To realistically depict the powder flow inside rotary tablet presses, custom-made tracer powder was developed. The applied method was proven to be appropriate as the tracer and bulk powder showed comparable properties. The RTDs of both materials were examined in two differently scaled rotary tablet presses and the influence of process parameters was determined. To analyze RTDs independent of the mass flow, the normalized variance was used to quantify intermixing. Substantial differences between both materials and tablet presses were found. Broader RTDs were measured for the poorer flowing MCC as well as for the production scale press. The obtained results can be used to improve the general understanding of powder flow inside rotary tablet presses and amplify scale-up and continuous production process development.

For the efficient and safe production of pharmaceutical tablets, a deep process understanding is of high importance. An essential process step during tableting is the die filling, as it is responsible for a consistent tablet weight and drug content. Furthermore, it affects the results of subsequent process steps, compaction and ejection, and thus critical quality attributes. This study focuses on understanding the influences of process parameters and material properties on die filling on a rotary tablet press. By the systematic variation in process parameters as the turret and paddle speeds as well as the fill and dosing depths, five formulations with differing properties are processed. Analysis of the normalized tablet weight, called filling yield, revealed different limitation mechanisms of the filling process, i.e., incomplete filled dies for certain parameter settings. Kinetic limitations occur due to a short residence time under the feed frame (filling time) caused by high turret speeds, which additionally induce high tablet weight variation coefficients. Characteristic maximum turret speeds at certain paddle speeds can be found to still achieve complete filling. At low turret speeds, densification of the powder inside the dies takes place, induced by two mechanisms: either high paddle speeds or high overfill ratios, or a combination of both. The challenge to fill the dies completely as well as avoid densification is dependent on material properties as the flowability. The mass discharge rate from an orifice was found to be in a linear correlation to the filling results of different formulations below complete filling.

Today, probiotics are predominantly used in liquid or semi-solid functionalized foods, showing a rapid loss of cell viability. Due to the increasing spread of antibiotic resistance, probiotics are promising in pharmaceutical development because of their antimicrobial effects. This increases the formulation requirements, e.g., the need for an enhanced shelf life that is achieved by drying, mainly by lyophilization. For oral administration, the process chain for production of tablets containing microorganisms is of high interest and, thus, was investigated in this study. Lyophilization as an initial process step showed low cell survival of only 12.8%. However, the addition of cryoprotectants enabled survival rates up to 42.9%. Subsequently, the dried cells were gently milled. This powder was tableted directly or after mixing with excipients microcrystalline cellulose, dicalcium phosphate or lactose. Survival rates during tableting varied between 1.4% and 24.1%, depending on the formulation and the applied compaction stress. More detailed analysis of the tablet properties showed advantages of excipients in respect of cell survival and tablet mechanical strength. Maximum overall survival rate along the complete manufacturing process was >5%, enabling doses of 6 × 108 colony forming units per gram (CFU gtotal-1), including cryoprotectants and excipients., Competing Interests: The authors declare no conflict of interest.

Myeloid-derived suppressor cells (MDSC) are induced by and accumulate within many histologically distinct solid tumors, where they promote disease by secreting angiogenic and immunosuppressive molecules. Although IL1β can drive the generation, accumulation, and functional capacity of MDSCs, the specific IL1β-induced inflammatory mediators contributing to these activities remain incompletely defined. Here, we identified IL1β-induced molecules that expand, mobilize, and modulate the accumulation and angiogenic and immunosuppressive potencies of polymorphonuclear (PMN)-MDSCs. Unlike parental CT26 tumors, which recruited primarily monocytic (M)-MDSCs by constitutively expressing GM-CSF- and CCR2-directed chemokines, IL1β-transfected CT26 produced higher G-CSF, multiple CXC chemokines, and vascular adhesion molecules required for mediating infiltration of PMN-MDSCs with increased angiogenic and immunosuppressive properties. Conversely, CT26 tumors transfected with IL1β-inducible molecules could mobilize PMN-MDSCs, but because they lacked the ability to upregulate IL1β-inducible CXCR2-directed chemokines or vascular adhesion molecules, additional PMN-MDSCs could not infiltrate tumors. IL1β-expressing CT26 increased angiogenic and immunosuppressive factors of tumor-infiltrating MDSCs, as did CT26 tumors individually transfected with G-CSF, Bv8, CXCL1, or CXCL5, demonstrating that mediators downstream of IL1β could also modulate MDSC functional activity. Translational relevance was indicated by the finding that the same growth factors, cytokines, chemokines, and adhesion molecules responsible for the mobilization and recruitment of PMN-MDSCs into inflammatory CT26 murine tumors were also coordinately upregulated with increasing IL1β expression in human renal cell carcinoma tumors. These studies demonstrated that IL1β stimulated the components of a multifaceted inflammatory program that produces, mobilizes, chemoattracts, activates, and mediates the infiltration of PMN-MDSCs into inflammatory tumors to promote tumor progression., (©2019 American Association for Cancer Research.)

A new methodology to segment the three-dimensional (3D) internal structure of Ibuprofen tablets from synchrotron tomography is presented, introducing a physically coherent trinarization for greyscale images of Ibuprofen tablets consisting of three phases: microcrystalline cellulose, Ibuprofen and pores. For this purpose, a hybrid approach is developed combining a trinarization by means of statistical learning with a trinarization based on a watershed algorithm. This hybrid approach allows us to compute microstructure characteristics of tablets using methods of statistical image analysis. A comparison with experimental results shows that there is a significant amount of pores which is below the resolution limit. At the same time, results from image analysis let us conjecture that these pores constitute the great majority of the surface between pores and solid. Furthermore, we compute microstructure characteristics, which are experimentally not accessible such as local percolation probabilities and chord length distribution functions. Both characteristics are meaningful in order to quantify the influence of tablet compaction on its microstructure. The presented approach can be used to get better insight into the relationship between production parameters and microstructure characteristics based on 3D image data of Ibuprofen tablets manufactured under different conditions and elucidate key effects on the strength and solubility kinetics of the final  formulation. LAY DESCRIPTION: A typical formulation of uniaxial compacted Ibuprofen tablets consist of a mixture of an excipient (microcrystalline cellulose) with an active ingredient (a ground fraction of Ibuprofen). The final mechanical strength of the tablet as well as the release kinetics are strongly influenced by the underlying microstructure, i.e. the spatial arrangement of the microcrystalline cellulose and Ibuprofen within the tablet. In order to optimize the performance of the tablet, it is important to investigate the relationship between its microstructure and the corresponding production parameters. For this purpose, 3D imaging is a powerful tool as it allows computing microstructural properties such as the internal arrangement, interconnectivity and pore location and distribution, characteristics that cannot be computed by experimental characterization techniques. In the present study, a new algorithm for an accurate trinarization of 3D image data obtained by synchrotron tomography is presented. Trinarization means that we reconstruct microcrystalline cellulose, Ibuprofen and pores on the basis of the 3D images, where one can only observe different greyscale values, but not the different constituents themselves. For this purpose, a hybrid approach combining a trinarization by means of artificial intelligence with a trinarization based on a geometrically motivated algorithm is developed. This hybrid approach allows to compute microstructure characteristics of tablets using image analysis. A comparison with experimental results shows that there is a significant amount of pores below the resolution limit. At the same time results from image analysis lead to the conjecture that these pores constitute the major part of the surface between pores and solid. Moreover, characteristics are computed by image analysis, which are meaningful in order to quantify the influence of tablet compaction parameters on its microstructure. The presented novel approach can be used to elucidate the relationship between production parameters and microstructure characteristics based on 3D image data of Ibuprofen tablets manufactured under different mixing, loading and processing conditions., (© 2019 The Authors Journal of Microscopy © 2019 Royal Microscopical Society.)

The embedding of nanoparticles in orodispersible films (ODFs) is an innovative strategy to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (API). As the films are supposed to disintegrate within seconds when placed in the mouth, the disintegration time of the ODFs as well as the dissolution behavior of the API are of great interest. This study introduces a new possibility for a model-based description of these film properties to enable a prediction for the process layout for the manufacturing of the nanoparticle-loaded ODFs. Furthermore, this fundamental understanding can provide information on process robustness as a tool applied in future Quality by Design (QbD) approaches. The disintegration times of the nanoparticle-containing ODFs were measured with the SFaB method (slide frame and ball) and could be mathematically described considering the impact of the particle load and the dry film thickness on the disintegration behavior. Furthermore, it is considered if the films are disintegrated at the calculated time with a probability of 50% or any other probability. Besides the disintegration time, a clear influence of film parameters like the particle load, size of the embedded particles, film thickness and sample sizes was shown which affect the dissolution rate of the API from the ODF. The second model developed in the study identified a clear correlation between the total surface area of API particles in the film and the dissolution rate of the API, to predict the time period needed to release the API embedded in the ODFs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In order to cope with the increasing number of multimorbid patients due to demographic changes, individualized polypill solutions must be developed. One promising tool is fused layer modeling (FLM) of dosage forms with patient-specific dose combinations and release individualization. As there are few approaches reported that systematically investigate the influence of high disperse active pharmaceutical ingredient (API) loads in filaments needed for FLM, this was the focus for the present study. Different filaments based on polyethylene oxide and hypromellose (HPMC) with different loads of theophylline as model API (up to 50 wt.%) were extruded with a twin-screw extruder and printed to dosage forms. Along the process chain, the following parameters were investigated: particle size and shape of theophylline; mechanical properties, microstructure, mass and content uniformity of filaments as well as dosage forms and the theophylline release from selected dosage forms. Especially for HPMC, increasing theophylline load enhanced the flexural strength of filaments whilst the FLM accuracy decreased inducing defects in microstructure. Theophylline load had no significant effect on the dissolution profile of HPMC-based dosage forms. Therefore, a thorough analysis of particle-induced effects is necessary to correlate mechanical properties of filaments, printability, and the dosage-and-release profile adjustment.

Orodispersible films (ODFs) have a high potential to accelerate the individualized medication. The films can be produced as drug-free templates and subsequently printed with an API (active pharmaceutical ingredient) solution or suspension according to the needs of the patient. While the printing technology already enables a precise dosing of fluids, there is still a high need of suitable, edible templates with elevated loading capacity. The structured orodispersible film templates (SOFTs) developed in this study should overcome this void. The SOFTs are pervaded with pores to realize a high API load into the film structure and possess a closed bottom side to prevent the printed fluids to pass through the film. They consist of a water-soluble cellulose derivative and are produced with the solvent casting method. This study focused on the influence of the formulation of the film casting mass on the film properties, like porosity and disintegration time due to changed pore sizes and numbers. Due to the porous film structure a mass load of up to 6.1 mg cm -2 could be realized already in SOFTs, but, higher loads are feasible. The mechanical film properties could further be improved by additional matrix material in the suspension formulation, also inhibiting particle agglomeration and aggregation during the drying process, and positively influencing the dissolution behavior of the applied nanoparticles. An application of a protection layer on top of the loaded SOFTs improves the handling safety by inhibiting contact to the API and it prevents a removal of the particles from the film surface., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In-die compression analysis is an effective method for the characterization of powder compressibility. However, physically unreasonable apparent solid fractions above one or apparent in-die porosities below zero are often calculated for higher compression stresses. One important reason for this is the neglect of solid compressibility and hence the assumption of a constant solid density. In this work, the solid compressibility of four pharmaceutical powders with different deformation behaviour is characterized using mercury porosimetry. The derived bulk moduli are applied for the calculation of in-die porosities. The change of in-die porosity due to the consideration of solid compressibility is for instance up to 4% for microcrystalline cellulose at a compression stress of 400 MPa and thus cannot be neglected for the calculation of in-die porosities. However, solid compressibility and further uncertainties from, for example the measured solid density and from the displacement sensors, are difficult or only partially accessible. Therefore, a mathematic term for the calculation of physically reasonable in-die porosities is introduced. This term can be used for the extension of common mathematical models, such as the models of Heckel and of Cooper & Eaton. Additionally, an extended in-die compression function is introduced to precisely describe the entire range of in-die porosity curves and to enable the successful differentiation and quantification of the compression behaviour of the investigated pharmaceutical powders.

Powder densification through uniaxial compaction is governed by a number of simultaneous processes taking place on a reduced time as the result of the stress gradients within the packing, as well as the frictional and adhesive forces between the powder and the die walls. As a result of that, a density and stiffness anisotropy is developed across the axial and radial directions. In this study, microindentation has been applied to assess and quantify the variation of the module of elasticity ( E m o d ) throughout the surface of cylindrical tablets. A representative set of deformation behaviors was analyzed by pharmaceutical excipients ranging from soft/plastic behavior (microcrystalline cellulose) over medium (lactose) to hard/brittle behavior (calcium phosphate) for different compaction pressures. The results of the local stiffness distribution over tablet faces depicted a linear and directly proportional tendency between a solid fraction and E m o d for the upper and lower faces, as well as remarkable stiffness anisotropy between the axial and radial directions of compaction. The highest extent of the stiffness anisotropy that was found for ductile grades of microcrystalline cellulose (MCC) in comparison with brittle powders has been attributed to the dual phenomena of overall elastic recovery and Poisson's effect on the relaxation kinetics. As a reinforcement of this analysis, the evolution of the specific surface area elucidated the respective densification mechanism and its implementations toward anisotropy. For ductile excipients, the increase in the contact surface area as well as the reduction and closing of interstitial pores explain the reduction of surface area with increasing compaction pressure. For brittle powders, densification evolves through fragmentation and the subsequent filling of voids.

Background: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions., Objective: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC)., Patients and Methods: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33 + HLADR - ) and CTL (CD8 + CD4 - ) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14 + CD15 - ), polymorphonuclear (PMN)-MDSC (CD14 - CD15 + ), and immature (I)-MDSC (CD14 - CD15 - ). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI., Results: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Guérin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1 + (%PDL1 + ) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1 + M- and I-MDSC. Although pre-treatment %PD1 + CTL did not predict response, a greater %PD1 + CTL within 9 weeks after ICI initiation correlated with objective response., Conclusions: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.

Antisolvent precipitation of poorly water-soluble drugs is a promising formulation technique to synthesize amorphous nanoparticles. The dissolution behavior of these nanoparticles is improved because of the high specific surface area and the amorphous state, leading to an enhanced bioavailability of the drug molecules. Nevertheless, stabilization of precipitated drug nanoparticles against agglomeration and recrystallization, which constitutes a key issue for further processing steps, has turned out to be a major challenge. For that reason, the present study presents a synthesis method to produce long-term stable amorphous ibuprofen nanoparticles via antisolvent precipitation. To reach this goal, a new precipitation method was developed: antisolvent melt precipitation (AMP). Formulation strategies (e.g. varying fraction of stabilizer) as well as process parameters (e.g. temperature) were under study to estimate their influence on particle size, size distribution, crystallinity, morphology and stability of synthesized drug nanoparticles., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Myeloid derived suppressor cells (MDSC) are heterogeneous immunosuppressive cells with potential predictive and prognostic roles in cancer. The association between MDSC, clinicopathologic factors, and pathologic response in patients with bladder urothelial carcinoma (UC) was explored., Methods: Peripheral blood or tissue were collected from patients with UC undergoing definitive surgery. MDSCs levels were measured in peripheral blood mononuclear cells and fresh tumor tissue. MDSCs were identified by flow cytometry and defined as total MDSC (T-MDSC) CD33+/HLADR-. From this population, 3 subsets were identified: polymorphonuclear-MDSC (PMN-MDSC) defined as CD33+/HLADR-/CD15+/CD14-, monocytic-MDSC (M-MDSC) defined as CD33+/HLADR-/CD15-/CD14+, and immature-MDSC (I-MDSC) defined as CD33+/HLADR-/CD15-/CD14-. MDSC populations were presented as % of live nucleated blood cells. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors, and pathologic complete response (pCR)., Results: 85 patients scheduled to undergo cystectomy from February 2015 through Dec 2016 were included. All patients had blood drawn for analysis and 23 patients had residual tumor tissue collected for analysis at the time of surgery. Of these 85, 74 (87%) were men with a median age at diagnosis of 68 (range: 44-87). Pure UC was the most common histology (75%); 28 (35%) patients had prior treatment with intravesical therapy and 36 (42%) were treated with neoadjuvant chemotherapy, primarily gemcitabine plus cisplatin (n = 24). On surgical pathology, 18 (21%) of the patients had pCR, 11 (13%) had positive lymph nodes, and 20 patients (24%) had lymphovascular invasion. Statistically significant associations were found between circulating MDSC levels and pCR rates (P<0.01), absolute neutrophil-lymphocyte ratio (P = 0.008), and histology (P = 0.01). Tumor % M-MDSCs were negatively associated with lymphovascular invasion (P = 0.04). There were no significant correlations between peripheral blood mononuclear cells and tumor MDSC subtypes., Conclusions: Blood and tissue MDSC levels correlate with several clinicopathologic factors and may predict for pCR. Future studies are needed to highlight the role of MDSC in predicting long-term outcomes and to determine the clinical implications of these findings., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Low aqueous solubility of active pharmaceutical ingredients presents a serious challenge in the development process of new drug products. This article provides an overview on some of the current approaches for the formulation of poorly water-soluble drugs with a special focus on strategies pursued at the Center of Pharmaceutical Engineering of the TU Braunschweig. These comprise formulation in lipid-based colloidal drug delivery systems and experimental as well as computational approaches towards the efficient identification of the most suitable carrier systems. For less lipophilic substances the preparation of drug nanoparticles by milling and precipitation is investigated for instance by means of microsystem-based manufacturing techniques and with special regard to the preparation of individualized dosage forms. Another option to overcome issues with poor drug solubility is the incorporation into nanospun fibers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The individualization of solid dosage forms to realize a flexible therapy for all patient groups is a topic which increasingly gains importance in pharmaceutical research. The goal of this study was to develop a nanoparticulate, instant orodispersible film (iODF) powder which can easily be reconstituted in water to cast ODFs containing an individualized concentration of an active pharmaceutical ingredient (API). It was shown that the processing of the film casing mass to iODF powders by spray drying provides the same advantageous film properties, particles sizes redispersed from the ODF and dissolution profiles as compared to the common production route. Due to the realization of nanoparticle loads up to 50wt.% in the iODF powders, high API loads (11.8mgcm -2 ) are achieved in final ODFs. The powders are well storable at different temperatures for at least three months and do not change their crystalline state during storage. Furthermore, dissolution of a defined amount of API from ODFs was found to be the fastest with the highest drug loads in the films., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-derived xenograft (PDX) model., Methods: RCC tumours were harvested during pre-treatment, response and escape phases. Direct anti-proliferative effects of sunitinib plus MEK inhibitor were assessed. Activation status (phosphorylation) of MEK1/2 and ERK1/2 was determined, myeloid-derived suppressor cells (MDSC) sub-fractions were quantitated and G-CSF was measured by ELISA., Results: During the response phase, tumours exhibited 91% reduction in volume, characterised by decreased expression of cell survival genes. After 4-week treatment, tumours developed resistance to sunitinib, associated with increased expression of pro-angiogenic and cell survival genes. During tumour escape, cellular movement, inflammatory response and immune cell trafficking genes were induced, along with intra-tumoural accumulation of MDSC. In this PDX model, either continuous treatment with sunitinib plus MEK inhibitor PD-0325901, or switching from sunitinib to PD-0325901 was effective. The combination of PD-0325901 with TKI suppressed intra-tumoural phospho-MEK1/2, phospho-ERK1/2 and MDSC., Conclusions: Continuous treatment with sunitinib alone did not maintain anti-tumour response; addition of MEK inhibitor abrogated resistance, leading to improved anti-tumour efficacy., Competing Interests: JHF received sponsored research support from Pfizer. BIR received research and consulting support from Pfizer. The remaining authors declare no conflict of interest.

Orodispersible films possess a great potential as a versatile platform for nanoparticle-loaded oral dosage forms. In this case, poorly water-soluble organic materials were ground in a stirred media mill and embedded into a polymer matrix. The aim of this study was the shortening of this manufacturing process by the integration of several process steps into a stirred media mill without facing disadvantages regarding the film quality. Furthermore, this process integration is time conserving due to the high stress intensities provided in the mill and applicable for high solids contents and high suspension viscosities. Two organic materials, the model compound Anthraquinone and the active pharmaceutical ingredient Naproxen were investigated in this study. Besides the impact of the film processing on the crystallinity of the particles in the orodispersible film, a particle load of up to 50% was investigated with the new developed processing route. Additionally, a disintegration test was developed, combining an appropriate amount of saliva substitute and a clear endpoint determination. In summary, high nanoparticle loads in orodispersible films with good particle size preservation after film redispersion in water as well as a manufacturing of the film casting mass within a few minutes in a stirred media mill was achieved., (Copyright © 2016 Elsevier B.V. All rights reserved.)