The need for new control strategies for particulate matter in parenterals.

An undesirable characteristic in lyophilized parenteral products is the potential presence of particulate matter in the final product, which may affect patient safety. In this study, quality risk management tools described in the International Conference on Harmonization Guideline Q9 were used to estimate the risks for a pharmaceutical manufacturing line, based on three critical quality attributes: (1) visible particulate matter; (2) lyo-cake collapse traces; and (3) lyo-cake melt-back traces. Together with a Process Failure Mode Effect Analysis (PFMEA), an input-output analysis of the individual unit operations identified seven major material classes of extrinsic particulate matter. In addition to the process assessment, an experimental investigation of the location of impurities in lyophilized products was performed. To that end, intentionally contaminated vials were examined to locate the particulate matter and its possible migration. The results emphasize the importance of a full transmission mode release testing since the particles may enter the interior of the lyo-cake. A theoretical explanation of the observed impurity locations is provided.

Substrate-Induced Phase of a Benzothiophene Derivative Detected by Mid-Infrared and Lattice Phonon Raman Spectroscopy.

The presence of a substrate-induced polymorph of 2,7-dioctyloxy[1]benzothieno[3,2-b]benzothiophene is probed in microscopic crystals and in thin films. Two experimental techniques are used: lattice phonon Raman and IR spectroscopy. The bulk crystal and substrate-induced phase have an entirely different molecular packing, and therefore, their Raman spectra are characteristic fingerprints of the respective polymorphs. These spectra can be unambiguously assigned to the individual polymorphs. Drop-cast and spin-coated thin films on solid substrates are investigated in the as-prepared state and after solvent-vapor annealing. Because Raman spectroscopy is less sensitive with decreasing film thickness, IR spectroscopy is shown to be a more feasible tool for phase detection. The surface-induced phase is mainly present in the as-prepared thin films, whereas the bulk phase is present after solvent-vapor annealing. This result suggests that the surface-induced phase is a metastable polymorph.

Adsorption Studies of Organophosphonic Acids on Differently Activated Gold Surfaces.

In this study, the formation of self-assembled monolayers consisting of three organophosphonic acids (vinyl-, octyl-, and tetradecylphosphonic acid) from isopropanol solutions onto differently activated gold surfaces is studied in situ and in real time using multiparameter surface plasmon resonance (MP-SPR). Data retrieved from MP-SPR measurements revealed similar adsorption kinetics for all investigated organophosphonic acids (PA). The layer thickness of the immobilized PA is in the range of 0.6-1.8 nm corresponding to monolayer-like coverage and correlates with the length of the hydrocarbon chain of the PA molecules. After sintering the surfaces, the PA are irreversibly attached onto the surfaces as proven by X-ray photoelectron spectroscopy and attenuated total reflection infrared and grazing incidence infrared spectroscopy. Potential adsorption modes and interaction mechanisms are proposed.

In situ PM-IRRAS of a glassy carbon electrode/deep eutectic solvent interface.

The interface of a 1 : 2 molar choline chloride/ethylene glycol deep eutectic solvent with a glassy carbon electrode has been investigated by polarization modulation reflection-absorption spectroscopy (PM-IRRAS). Temporal spectral changes at open circuit potential show the experiments to be surface sensitive and indicate slow adsorption of electrolyte molecules on the electrode surface. In situ spectroelectrochemical PM-IRRAS measurements reveal characteristic potential-dependent changes of band intensities and wavenumber-shifts in the surface spectra. The potential dependent spectral changes are discussed in terms of adsorption, reduction, desorption and reorientation of choline cations at the interface. Analogies are drawn to the ionic layer structure proposed for the architecture of electrode/ionic liquid interfaces. The results show that in situ PM-IRRAS is generally applicable to glassy carbon electrodes and to electrode interfaces with deep eutectic solvents.

Vacancy formation on C60/Pt (111): unraveling the complex atomistic mechanism.

The interaction of fullerenes with transition metal surfaces leads to the development of an atomic network of ordered vacancies on the metal. However, the structure and formation mechanism of this intricate surface reconstruction is not yet understood at an atomic level. We combine scanning tunneling microscopy, high resolution and temperature programmed-x-ray photoelectrons spectroscopy, and density functional theory calculations to show that the vacancy formation in C60/Pt(111) is a complex process in which fullerenes undergo two significant structural rearrangements upon thermal annealing. At first, the molecules are physisorbed on the surface; next, they chemisorb inducing the formation of an adatom-vacancy pair on the side of the fullerene. Finally, this metastable state relaxes when the adatom migrates away and the vacancy moves under the molecule. The evolution from a weakly-bound fullerene to a chemisorbed state with a vacancy underneath could be triggered by residual H atoms on the surface which prevent a strong surface-adsorbate bonding right after deposition. Upon annealing at about 440 K, when all H has desorbed, the C60 interacts with the Pt surface atoms forming the vacancy-adatom pair. This metastable state induces a small charge transfer and precedes the final adsorption structure.

Imaging ellipsometry based method and algorithm for the analysis of fiber-fiber bonds in a paper network.

The measurement of the bonded area of pulp fibers has been an unsolved issue in paper science for more than 40 years. By the use of an established pulp fiber model, and a 4 × 4 transfer matrix formalism we simulated the optical behavior of pulp fibers in a modified imaging ellipsometer, and we demonstrate that there are rather strong symmetries in the ellipsometric angles Ψ and Δ when comparing single fibers, unbonded fiber crossings, and fiber-fiber bonds. Based on these symmetries we propose and test an algorithm that allows to distinguish the three cases (single fibers, unbonded fiber crossings, and fiber-fiber bonds) in the analysis of ellipsometric data.

The Interaction of Cellulose Thin Films With Small Organic Molecules-Comparability of Two Inherently Different Methods.

Paper is the material of choice for a large range of applications because it has many favorable environmental and economic characteristics. Especially in the packaging sector of dry goods and food products, paper has found unique applications. For that purpose, it has to fulfill certain requirements: Primarily it should protect the packaged goods. In order to ensure the compliance of a paper packaging, its interactions with the packaged goods should be investigated. Therefore, it is of utmost importance to understand how the paper interacts with chemicals of different nature and what factors influence these interactions-be that the nature of the paper or the characteristics of the substances. In this study, we investigated the surface interactions of cellulose thin films with n-decane and deuterated methanol using two different analytical methods: headspace solid-phase microextraction with gas chromatography and flame ionization detection (HS-SPME-GC/FID) and temperature-programmed desorption (TPD). Cellulose thin films were characterized with contact angle and FT-IR measurements and successfully applied as model systems for real paper samples. Regarding the interactions of the cellulose films with the model compounds, the two inherently different methods, HS-SPME-GC/FID and TPD, provide very comparable results. While the nonpolar n-decane was readily released from the cellulose films, the polar model compound deuterated methanol showed a strong interaction with the polar cellulose surface.

Quantification and Imaging of Nanoscale Contact with Förster Resonance Energy Transfer.

Adhesion is caused by molecular interactions that only take place if the surfaces are in nanoscale contact (NSC); i.e., the distance between the surfaces is in the range of 0.1-0.4 nm. However, there are several difficulties measuring the NSC between surfaces, mainly because regions that appear to be in full contact at low magnification may show no NSC when observed at higher magnifications. Thus, the measurement area of NSC is very small with imaging techniques, and an experimental technique to evaluate NSC for large contact areas has not been available thus far. Here, we are proposing Förster resonance energy transfer (FRET) spectroscopy/microscopy for this purpose. We demonstrate that NSC in a distance range of 1-10 nm can be evaluated. Our experiments reveal that, for thin films pressed under different loads, NSC increases with the applied pressure, resulting in a higher FRET signal and a corresponding increase in adhesion force/energy when separating the films. Furthermore, we show that local variations in molecular contact can be visualized with FRET microscopy. Thus, we are introducing a spectroscopic technique for quantification (FRET spectroscopy) and imaging (FRET microscopy) of NSC between surfaces, demonstrated here for the application of surface adhesion. This could be of interest for all fields where adhesion or nanoscale surface contact are playing a role, for example, soft matter, biological materials, and polymers, but also engineering applications, like tribology, adhesives, and sealants.

X-ray imaging: A potential enabler of automated particulate detection and cake-structure analysis in lyophilized products?

The presence of particulate matter in parenteral products is a major concern since it affects the patients' safety and is one of the main reasons for product recalls. Conventional quality control is based on a visual inspection, which is a labour-intensive task. Limited to clear solutions and the surface of lyophilised products, it cannot be applied to opaque containers. This study assesses the application of X-ray imaging for detecting the particulate matter in a pharmaceutical lyophilized product. The most common types of particulates (i.e., steel, glass, lyo stopper, polymers and organics in different size classes) were intentionally spiked in vials. After optimizing all relevant parameters of the X-ray set-up, all classes of particulates were detected. At the same time, due to contrast enhancement, the inherent structures of lyophilized cake became obvious. This work addresses the potential and limits of X-ray technology in that regard, paving the way for automated image-based particulate matter detection. Moreover, this paper discusses using this approach to predict critical quality attributes (CQAs) of the drug product based on the cake structure attributes.

Spectroscopic Investigation of DCCH and FTSC as a potential pair for Förster Resonance Energy Transfer in different solvents.

Two molecules, 7-(diethylamino)coumarin-3-carbohydrazide (DCCH) and fluorescein-5-thiosemicarbazide (FTSC) were investigated in different solvents, under varying pH conditions regarding their spectroscopic properties for the usage as a Förster Resonance Energy Transfer (FRET) pair to study the molecular interaction between cellulosic surfaces. All the relevant spectroscopic properties to determine the Förster distance were measured and the performance as a FRET system was checked. From the results, it is clear that the environmental conditions need to be accurately controlled as both, but especially the FTSC dyes are sensitive to changes. For high enough concentrations positive FRET systems were observed in DMF, DMSO, H2O, THF and alkaline DMF. However due to the low quantum yield of the unmodified DCCH throughout the investigated parameter range and the strong environmental dependency of FTSC, both dyes are not preferable for being used in a FRET system for studying interaction between cellulosic surfaces.

A new method for performing polarization modulation infrared reflection-adsorption spectroscopy of surfaces.

A new and relatively simple polarization modulation technique is presented and tested that enables the whole spectral range to be detected between 400 and 4000 cm(-1). This experiment is conventionally carried out using a photoelastic modulator that modulates incident plane polarized light through 90 degrees . This suffers from the drawback that it enables spectra to be collected only over a relatively narrow spectral range. As an alternative, a polarizer is placed in the beam and oriented at 45 degrees to the sample normal. This produces incident radiation fluxes with identical intensities for both s- and p-polarized light. A second polarizer is then modulated through 90 degrees and the surface spectrum is then extracted in the usual manner from the difference between these signals, normalized to their sum. The method is demonstrated for a self-assembled monolayer of 11-mercapto-undecanoicacid (11-MUA) on gold on mica, and it is shown that, while the resulting spectra are extremely sensitive to optical alignment, the method yields spectra that are in excellent agreement with published data.

Simple method for the quantitative analysis of thin copolymer films on substrates by infrared spectroscopy using direct calibration.

The chemical composition of a copolymer drives many important material properties and quantification in terms of comonomer volume fraction is thus of practical relevance for many studies. Infrared spectroscopy is one of the most common techniques for compositional analysis but it usually relies on manual evaluation of baselines and peak heights, which can be rather inaccurate and become a laborious task when having multiple spectra to evaluate. On the contrary, Maxwell's theory of electrodynamics can be used to calculate the complex index of refraction from measured spectra promising a more accurate quantification. Since this procedure is rather involved, we propose a simple in-house developed IR-quantification routine to automatically evaluate the comonomer volume fractions of thin copolymer films by using the Bouguer-Lambert-Beer approximation after correcting the baseline of all absorbance spectra automatically. This method was experimentally evaluated on over 40 thin polymeric coatings synthesized by initiated chemical vapor deposition on silicon substrates. The samples comprised a wide range of different compositions and were synthesized from four different monomers, with single films consisting of up to three components. All data obtained by our routine was compared with data from spectroscopic ellipsometry and with X-ray photoelectron spectroscopy data of selected samples. The comparisons show that the IR-quantification routine reliably evaluated the polymer composition even when the involved comonomers exhibited similar chemistry, as it is the case for methacrylic acid cross-linked with ethylene glycol dimethacrylate.

Comprehensive analysis of individual pulp fiber bonds quantifies the mechanisms of fiber bonding in paper.

The process of papermaking requires substantial amounts of energy and wood consumption, which contributes to larger environmental costs. In order to optimize the production of papermaking to suit its many applications in material science and engineering, a quantitative understanding of bonding forces between the individual pulp fibers is of importance. Here we show the first approach to quantify the bonding energies contributed by the individual bonding mechanisms. We calculated the impact of the following mechanisms necessary for paper formation: mechanical interlocking, interdiffusion, capillary bridges, hydrogen bonding, Van der Waals forces, and Coulomb forces on the bonding energy. Experimental results quantify the area in molecular contact necessary for bonding. Atomic force microscopy experiments derive the impact of mechanical interlocking. Capillary bridges also contribute to the bond. A model based on the crystal structure of cellulose leads to values for the chemical bonds. In contrast to general believe which favors hydrogen bonding Van der Waals bonds play the most important role according to our model. Comparison with experimentally derived bond energies support the presented model. This study characterizes bond formation between pulp fibers leading to insight that could be potentially used to optimize the papermaking process, while reducing energy and wood consumption.

What holds paper together: nanometre scale exploration of bonding between paper fibres.

Paper, a man-made material that has been used for hundreds of years, is a network of natural cellulosic fibres. To a large extent, it is the strength of bonding between these individual fibres that controls the strength of paper. Using atomic force microscopy, we explore here the mechanical properties of individual fibre-fibre bonds on the nanometre scale. A single fibre-fibre bond is loaded with a calibrated cantilever statically and dynamically until the bond breaks. Besides the calculation of the total energy input, time dependent processes such as creep and relaxation are studied. Through the nanometre scale investigation of the formerly bonded area, we show that fibrils or fibril bundles play a crucial role in fibre-fibre bonding because they act as bridging elements. With this knowledge, new fabrication routes can be deduced to increase the strength of an ancient product that is in fact an overlooked high-tech material.

Adhesion of cellulose fibers in paper.

The surface topography of paper fibers is studied using atomic force microscopy (AFM), and thus the surface roughness power spectrum is obtained. Using AFM we have performed indentation experiments and measured the effective elastic modulus and the penetration hardness as a function of humidity. The influence of water capillary adhesion on the fiber-fiber binding strength is studied. Cellulose fibers can absorb a significant amount of water, resulting in swelling and a strong reduction in the elastic modulus and the penetration hardness. This will lead to closer contact between the fibers during the drying process (the capillary bridges pull the fibers into closer contact without storing up a lot of elastic energy at the contacting interface). In order for the contact to remain good in the dry state, plastic flow must occur (in the wet state) so that the dry surface profiles conform to each other (forming a key-and-lock type of contact).

Joint strength measurements of individual fiber-fiber bonds: an atomic force microscopy based method.

We are introducing a method to measure tensile strength of individual fiber-fiber bonds within a breaking force range of 0.01 mN-1 mN as well as the energy consumed during breaking. Until now, such a method was not available. Using a conventional atomic force microscope and a specifically designed sample holder, the desired force and the breaking behavior can be analyzed by two different approaches. First, dynamic loading can be applied, where force-versus-distance curves are employed to determine the proportions of elastic energy and energy dissipated in the bond. Second, static loading is utilized to study viscoelastic behavior and calculate viscoelastic energy contributions. To demonstrate the capability of the proposed method, we are presenting results for breaking strength of kraft pulp fiber-fiber bonds in tensile opening mode. The procedure is by no means restricted to cellulose fibers, it has the potential to quantify joint strength of micrometer-sized fibers in general.

Determination of noise-free optical constants in the infrared by Kramers-Kronig transformation of the reflectance ratio in s- and p-polarization.

A method for Kramers-Kronig transformation of the reflectance ratio of s- and p-polarized light is discussed. The method is well suited for the determination of the optical constants of isotropic samples such as pellets prepared from powders. An algorithm is given that performs the transformation, including extrapolation at the data margins and an automated data fitting routine, that can handle very complex spectra of, e.g., biomacromolecules such as cellulose to obtain noise free spectra. Criteria for evaluation of the quality of the obtained data are given, and experimental data for cellulose II and xylane are presented.

A study on the formation and thermal stability of 11-MUA SAMs on Au(111)/mica and on polycrystalline gold foils.

In this article we present a comprehensive study of 11-mercaptoundecanoic acid self-assembled monolayer (SAM) formation on gold surfaces. The SAMs were prepared in ethanolic solution, utilizing two different substrates: Au(111)/mica and polycrystalline gold foils. Several experimental methods (X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and atomic force microscopy) reveal a well-defined SAM. The main focus of this work, however, was to test the stability of these SAMs by thermal desorption spectroscopy. The spectra show different desorption peaks indicating different adsorption states and/or decomposition products on the surface. The assumed monolayer peak, which can be attributed to desorption of the intact molecule, is detected at 550 K. Further desorption peaks can be found, which result, e.g., from cracking of the S-C bond on the surface, depending on the substrate quality and on the residence time under ambient conditions.

A two-step method to covalently bind biomolecules to group-IV semiconductors: Si(111)/1,2-epoxy-9-decene/esterase.

A versatile two-step method has been developed that allows linking of biomolecules covalently to hydrogen-terminated group-IV semiconductors by means of epoxy-alkenes. First, the terminal C==C double bond of the alkene forms a covalent bond with the silicon, germanium, or diamond surface by UV-mediated hydrosilylation. The terminal oxirane moiety then reacts with the biomolecule. As a model system, we investigated the attachment of an esterase B to a Si(111) surface by means of the linker molecule 1,2-epoxy-9-decene. Samples were characterized by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy. The immobilized enzyme retained its activity and exhibited good long-term stability.