Large area ion beam sputtered dielectric ultrafast mirrors for petawatt laser beamlines.

The latest advances in petawatt laser technology within the ELI Beamlines project have stimulated the development of large surface area dielectrically coated mirrors meeting all demanding requirements for guiding the compressed 30 J, 25 fs HAPLS laser beam at 10 Hz repetition rate and a center wavelength of 810 nm entirely in vacuum. We describe the production and evaluation of Ta2O5/HfO2/SiO2 ion beam sputtered coated (440 × 290 × 75) mm3 beam transport mirrors. No crazing was observed after thirty vacuum-air cycles. A laser induced damage threshold of 0.76 J/cm2 (fluence on mirror surface) was achieved and maintained at high shot rates.

The effect of relative humidity and formulation variables on chewable xylitol-sorbitol tablets.

Changing relative humidity levels challenge the manufacturing of chewable xylitol-sorbitol based tablets. The aim of the study is to investigate how the formulation of chewable xylitol-sorbitol tablets affects the properties of the powder blends and the tablets in an environment of different relative humidity levels. In all, 30 batches containing different ratios of sorbitol, xylitol and magnesium stearate were prepared at three different relative humidity levels. Powder blends were made into tablets using an instrumented eccentric tableting machine. To demonstrate the effect of variables on powder blend and tablet properties, multiple linear regression analysis was performed. It was found that xylitol-sorbitol powder blends and tablets benefitted from the large amount of magnesium stearate, and the high lubricant level negatively affected the quality of the tablets only at high relative humidity. In the presence of high environmental humidity, the amount of sorbitol in the powder mixture must be limited in order to prevent sticking whereas at low relative humidity, higher content of sorbitol is needed to decrease the friability of tablets. Results indicate that alternating relative humidity levels truly challenge the production of xylitol-sorbitol based tablets and if the humidity is not controllable, there is a need for additional filler-binders.

Predicting tablet tensile strength with a model derived from the gravitation-based high-velocity compaction analysis data.

In the present study, a model was developed to estimate tablet tensile strength utilizing the gravitation-based high-velocity (G-HVC) method introduced earlier. Three different formulations consisting of microcrystalline cellulose (MCC), dicalcium phosphate dihydrate (DCP), hydroxypropyl methylcellulose (HPMC), theophylline and magnesium stearate were prepared. The formulations were granulated using fluid bed granulation and the granules were compacted with the G-HVC method and an eccentric tableting machine. Compaction energy values defined from G-HVC data predicted tensile strength of the tablets surprisingly well. It was also shown, that fluid bed granulation improved the compaction energy intake of the granules in comparison to respective physical mixtures. In addition, general mechanical properties and elastic recovery were also examined for all samples. In this study it was finally concluded, that the data obtained by the method was of practical relevance in pharmaceutical formulation development.

Pectin and Mucin Enhance the Bioadhesion of Drug Loaded Nanofibrillated Cellulose Films.

PURPOSE: Bioadhesion is an important property of biological membranes, that can be utilized in pharmaceutical and biomedical applications. In this study, we have fabricated mucoadhesive drug releasing films with bio-based, non-toxic and biodegradable polymers that do not require chemical modifications. METHODS: Nanofibrillar cellulose and anionic type nanofibrillar cellulose were used as film forming materials with known mucoadhesive components mucin, pectin and chitosan as functional bioadhesion enhancers. Different polymer combinations were investigated to study the adhesiveness, solid state characteristics, film morphology, swelling, mechanical properties, drug release with the model compound metronidazole and in vitro cytotoxicity using TR146 cells to model buccal epithelium. RESULTS: SEM revealed lamellar structures within the films, which had a thickness ranging 40-240 µm depending on the film polymer composition. All bioadhesive components were non-toxic and showed high adhesiveness. Rapid drug release was observed, as 60-80% of the total amount of metronidazole was released in 30 min depending on the film formulation. CONCLUSIONS: The liquid molding used was a straightforward and simple method to produce drug releasing highly mucoadhesive films, which could be utilized in treating local oral diseases, such as periodontitis. All materials used were natural biodegradable polymers from renewable sources, which are generally regarded as safe.

Interdependence of particle properties and bulk powder behavior of indomethacin in quench-cooled molten two-phase solid dispersions.

Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus®) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus® significantly improved the dissolution rate of IND at pH 6.8 (79.9 ±â€¯0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus® in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau.

Examining mechanical properties of various pharmaceutical excipients with the gravitation-based high-velocity compaction analysis method.

The compression physics of powders must be considered when developing a suitable tablet formulation. In the present study, the gravitation-based high-velocity method was utilized to analyze mechanical properties of eight common pharmaceutical excipients: two grades of lactose, anhydrous glucose, anhydrous calcium hydrogen phosphate, three grades of microcrystalline cellulose and starch. Samples were compressed five times consecutively with varying pressure and speed so that Setup A produced higher pressure and longer contact time than Setup B. The important parameters obtained from samples were porosity profiles, compaction pressure, contact time, internal energy change and the amount of elastic recovery. All acquired data was only based on distance-time profile of the compression event. Lactose and glucose fragmented effectively while calcium hydrogen phosphate remained in rearrangement phase, due to its hardness and insufficient pressure applied. Microcrystalline cellulose samples showed plastic behaviour and starch was most elastic of all the samples. By utilizing the method, examined excipients could be categorized according to their compression behaviour in an accurate and cost-efficient manner.

Introducing a novel gravitation-based high-velocity compaction analysis method for pharmaceutical powders.

With modern tableting machines large amounts of tablets are produced with high output. Consequently, methods to examine powder compression in a high-velocity setting are in demand. In the present study, a novel gravitation-based method was developed to examine powder compression. A steel bar is dropped on a punch to compress microcrystalline cellulose and starch samples inside the die. The distance of the bar is being read by a high-accuracy laser displacement sensor which provides a reliable distance-time plot for the bar movement. In-die height and density of the compact can be seen directly from this data, which can be examined further to obtain information on velocity, acceleration and energy distribution during compression. The energy consumed in compact formation could also be seen. Despite the high vertical compression speed, the method was proven to be cost-efficient, accurate and reproducible.

The formation and physical stability of two-phase solid dispersion systems of indomethacin in supercooled molten mixtures with different matrix formers.

Amorphous solid dispersions (SDs) are a promising approach to improve the dissolution rate of and oral bioavailability of poorly water-soluble drugs. In some cases multi-phase, instead of single-phase, SD systems with amorphous drug are obtained. While it is widely assumed that one-phase amorphous systems are desirable, two-phase systems may still potentially exhibit enhanced stability and dissolution advantages over undispersed systems. The objective of the present study was to understand the solid-state properties of two-phase SDs with amorphous drug and their relation to physical stability. Two different types of excipients for SD formation were used, one being a polymer and the other a small molecule excipient. The supercooled molten SDs of a poorly water-soluble indomethacin (IND) with a graft copolymer, Soluplus® (SOL) and sugar alcohol, xylitol (XYL) were prepared. Supercooled molten SDs of IND with SOL were two-phase glassy suspension in which the amorphous drug was dispersed in an amorphous polymer matrix. A short-term aging of the SDs led to the formation of glassy suspensions where the crystalline drug was dispersed in an amorphous polymer matrix. These were physically stable at room temperature for the time period studied (RT, 23±2°C), but aging at high-humidity conditions (75% RH) recrystallization to metastable α-IND occurred. Interestingly, the SDs with XYL were two-phase amorphous precipitation systems in which the drug was in an amorphous form in the crystalline sugar alcohol matrix. The SDs of IND and XYL exhibited fast drug recrystallization. In conclusion, the preparation method of two-phase systems via co-melting in association with the rapid quench cooling is a feasible method for the formulation of poorly water-soluble drugs. The physical stability of these two-phase systems, however, is dependent on the carrier material and storage conditions.

Fourier-transform spectral interferometry for in situ group delay dispersion monitoring of thin film coating processes.

A fast Fourier-based measurement system to determine phase, group delay, and group delay dispersion during optical coating processes is proposed. The in situ method is based on a Michelson interferometer with a broad band light source and a very fast spectrometer. To our knowledge, group delay dispersion measurements directly on the moving substrates during a deposition process for complex interference coatings have been demonstrated for the first time. Especially for the very precise production of chirped mirrors it is advantageous to get information about the phase properties of the grown layer stack to react on errors and retrieve more information about the coating process.

Monitoring the recrystallisation of amorphous xylitol using Raman spectroscopy and wide-angle X-ray scattering.

In this paper we present a fast model system for monitoring the recrystallization of quench-cooled amorphous xylitol using Raman spectroscopy and wide-angle X-ray scattering. The use of these two methods enables comparison between surface and bulk crystallization. Non-ordered mesoporous silica micro-particles were added to the system in order to alter the rate of crystallization of the amorphous xylitol. Raman measurements showed that adding silica to the system increased the rate of surface crystallization, while X-ray measurements showed that the rate of bulk crystallization decreased. Using this model system it is possible to measure fast changes, which occur in minutes or within a few hours. Raman-spectroscopy and wide-angle X-ray scattering were found to be complementary techniques when assessing surface and bulk crystallization of amorphous xylitol.

High-Speed Intrinsic Dissolution Rate in One Minute Using the Single-Particle Intrinsic Dissolution Rate Method.

Intrinsic dissolution rate (IDR) has traditionally been determined from a constant surface area of a substance. Here we present an optofluidic single-particle intrinsic dissolution rate (SIDR) method, by means of which real-time determination of IDR from continuously changing effective surface areas of dissolving individual microparticles, is possible. The changing surface area of the individual microparticles is characterized through continuous random orientation 3D particle morphology characterization during the dissolution process. Using noninvasive optical monitoring and nonspecific image analysis, we determined IDRs of a diverse set of substances from individual pure-substance microparticles (14-747 µg) with an average relative standard deviation of 9.4%. A linear fit between SIDR and literature equilibrium solubility values (R(2) = 0.999) was achieved and kinetic solubility equivalent SIDRs were obtained, for all substances, in as little as 1 min. Such miniaturized methods could become valuable tools in drug discovery, by providing resource sparing higher quality data acquisition means to replace current high-throughput solubility methods.

Non-destructive assessment of mechanical properties of microcrystalline cellulose compacts.

In the present study the mechanical properties of microcrystalline cellulose compacts compressed were studied. The resistance to crushing was tested using diametral compression testing and apparent Young's modulus was determined using consecutive uniaxial compression of the full cross-sectional area of single tablets. As non-elastic deformation during the first compression cycle and reverse plasticity were discovered, the loading phase of the second compression cycle was used to determine Young's modulus. The relative standard deviation of 10 consecutive measurements was 3.6%. The results indicate a direct correlation between crushing strength and Young's modulus, which found further support when comparing surface roughness data and radial recovery of the tablets to Young's modulus. The extrapolated elastic modulus at zero-porosity was found to be 1.80±0.08 GPa, which is slightly lower than previously reported values, confirming the complexity of measuring the elastic properties of microcrystalline cellulose compacts. The method can be used for non-destructive assessment of mechanical properties of powder compacts for example during storage studies.

On-chip optofluidic single-particle method for rapid microscale equilibrium solubility screening of biologically active substances.

Solubility is the primary physicochemical property determining the absorption and bioavailability of substances. Here, we present an optofluidic single-particle technique for microscale equilibrium solubility determination, based on on-chip hydrodynamic particle trapping and optical particle size monitoring. The method combines the rapidity, universality, and substance sparing nature of physical analysis, with the accuracy traditionally associated with chemical analysis. Applying the diffusion layer theory, we determined the equilibrium solubility from individual pure substance microparticles of as little as 14 µg in initial mass, in a matter of seconds to minutes. The reduction in time and substance consumption, when compared to the golden standard method, is above 2 orders of magnitude. With a simultaneous improvement above 3-fold in accuracy of the solubility data, the applicability of optofluidics based analytics for small-scale high-throughput quantitative solubility and biological activity screening is demonstrated.

Optical microscopy as a comparative analytical technique for single-particle dissolution studies.

Novel, simple and cost effective methods are needed to replace advanced chemical analytical techniques, in small-scale dissolution studies. Optical microscopy of individual particles could provide such a method. The aim of the present work was to investigate and verify the applicability of optical microscopy as an analytical technique for drug dissolution studies. The evaluation was performed by comparing image and chemical analysis data of individual dissolving particles. It was shown that the data obtained by image analysis and UV-spectrophotometry produced practically identical dissolution curves, with average similarity and difference factors above 82 and below 4, respectively. The relative standard deviation for image analysis data, of the studied particle size range, varied between 1.9% and 3.8%. Consequently, it is proposed that image analysis can be used, on its own, as a viable analytical technique in single-particle dissolution studies. The possibility for significant reductions in sample preparation, operational cost, time and substance consumption gives optical detection a clear advantage over chemical analytical methods. Thus, image analysis could be an ideal and universal analytical technique for rapid small-scale dissolution studies.

Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets.

Continuous manufacturing gains more and more interest within the pharmaceutical industry. The International Conference of Harmonisation (ICH) states in its Q8 'Pharmaceutical Development' guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product performance over a range of raw material attributes, manufacturing process options and process parameters. This fits further into the Process Analytical Technology (PAT) and Quality by Design (QbD) framework. The present study evaluates the effect of variation in critical raw material properties on the critical quality attributes of granules and tablets, produced by a continuous from-powder-to-tablet wet granulation line. The granulation process parameters were kept constant to examine the differences in the end product quality caused by the variability of the raw materials properties only. Theophylline-Lactose-PVP (30-67.5-2.5%) was used as model formulation. Seven different grades of theophylline were granulated. Afterward, the obtained granules were tableted. Both the characteristics of granules and tablets were determined. The results show that differences in raw material properties both affect their processability and several critical quality attributes of the resulting granules and tablets.

Calculation of optical and electronic properties of modeled titanium dioxide films of different densities.

The electronic and optical properties of TiO2 atomic structures representing simulated thin films have been investigated using density functional theory. Suitable model parameters and system sizes have been identified in advance by validation of the results with experimental data. Dependencies of the electronic band gap and the refractive index have been calculated as a function of film density. The results of the performed calculations have been compared to characterized optical properties of titania single layers deposited using different coating techniques. The modeled dependencies are consistent with experimental observations, and absolute magnitudes of simulated values are in agreement with measured optical data.

Relation of optical properties and femtosecond laser damage resistance for Al2O3/AlF3 and Al2O3/SiO2 composite coatings.

We report on the realization of aluminum oxyfluoride thin films and alumina/silica mixture coatings with different ratios by ion beam sputtering. The atomic compositions quantified by energy dispersive x-ray spectroscopy are correlated with the optical properties calculated from spectrophotometry and laser calorimetry measurements. Furthermore, the femtosecond laser damage resistance (τ=400 fs) of single layers is investigated in the infrared at 1030 nm and in the ultraviolet at 343 nm wavelengths. Experimental results on the wavelength scaling of the laser-induced damage threshold for oxyfluoride and oxide composite coatings are presented.

Laser-induced damage in composites of scandium, hafnium, aluminum oxides with silicon oxide in the infrared.

The laser-induced damage of mixtures of Sc2O3, HfO2, Al2O3 with SiO2 has been characterized in the infrared for both nanosecond and subpicosecond pulses. Laser-induced damage thresholds (LIDTs) are reported and discussed versus band gap for different compositions. The distributions versus fluence of nanosecond damage precursor densities are extracted fitting damage probability curves. Two models are used: first, a statistical approach, i.e., direct calculation of damage precursor density from damage probability, and second a thermal model based on absorption of initiator. The results show a good agreement. The nature, shape, and size of these precursors are discussed. The critical temperature in the thermal model is dependent on the band gap energy.

Design and realization of advanced multi-index systems.

Practically all thin film systems for normal incidence can be realized using only two-layer materials. But for oblique incidence, polarization effects occur, designs may become complex, and polarization control is difficult or impossible to achieve. Here multi-index or gradient designs offer additional degrees of freedom, and can simplify or even enable challenging designs. Such gradient thin film stacks can be designed ab initio without any start or index profile approximations using a new design software developed by Carl Zeiss. With this software, a rugate omnidirectional AR coating was calculated and transferred to three different multi-index systems. All three examples were realized using ion beam sputter technology, and characterized at Laser Zentrum Hannover. Here we present comparative measurements of the optical performance together with femtosecond laser-induced damage threshold measurements.

Rapid interferometric imaging of printed drug laden multilayer structures.

The developments in printing technologies allow fabrication of micron-size nano-layered delivery systems to personal specifications. In this study we fabricated layered polymer structures for drug-delivery into a microfluidic channel and aimed to interferometrically assure their topography and adherence to each other. We present a scanning white light interferometer (SWLI) method for quantitative assurance of the topography of the embedded structure. We determined rapidly in non-destructive manner the thickness and roughness of the structures and whether the printed layers containing polymers or/and active pharmaceutical ingredients (API) adhere to each other. This is crucial in order to have predetermined drug release profiles. We also demonstrate non-invasive measurement of a polymer structure in a microfluidic channel. It shown that traceable interferometric 3D microscopy is a viable technique for detailed structural quality assurance of layered drug-delivery systems. The approach can have impact and find use in a much broader setting within and outside life sciences.