Search

Background: Currently, the equivalence and the substitutability of two inhaled medications are mainly driven by comparability of doses, in vitro performance, therapeutic equivalence and sameness, and handling of the inhalers. The packaging configuration is usually not considered as a factor. Methods: Two capsule-based inhaled tiotropium-containing products that differ by their primary packaging configurations (blister versus bottle) were compared in terms of potential handling and resulting storage errors due to unintentional misuse. Use error scenarios were identified and investigated for both the blister-packaged tiotropium and the bottled tiotropium capsules. The impact of the air exposure resulting from the packaging interaction errors was evaluated in vitro using fine particle dose (FPD) and delivered dose. Results: Numbers of potential errors and criticality in terms of the potential effect impact on the FPD were larger for the bottled product (between 40% and 90% loss on FPD related to initial dose). The loss of FPD could significantly impact the amount of medication that can actually reach the patient's lungs. Conclusion: When considering prescribing an inhaled medication, the specifics of the packaging and the patient's abilities and situation shall be taken into account to minimize possible handling and subsequent dosing errors.

Background The identification of different (pseudo) polymorphs of an active pharmaceutical ingredient in dry powder formulations is of importance during development and entire product lifecycle, e.g., quality control. Whereas determination of polymorphic differences of pure substances is rather easy, in dry powder formulations, it is generally difficult and the difficulties increase particularly, if the substance of interest is present only in low concentrations in the formulation. Such a formulation is Spiriva® inhalation powder (Boehringer Ingelheim), which contains only 0.4 w/w% of the active pharmaceutical ingredient tiotropium bromide monohydrate in a matrix of α-lactose monohydrate as excipient. Methods In this study, identification of 0.4 w/w% tiotropium bromide in the dry powder formulation was examined by X-ray powder diffraction (XRPD) using a synchrotron radiation source and the results were compared with the conventional laboratory XRPD measurements. Results The detection limit of tiotropium bromide by the laboratory XRPD was around 2–5 w/w%, and hence, detection of 0.4 w/w% tiotropium bromide was impossible. The synchrotron XRPD was capable to detect significantly lower level of tiotropium bromide by at least an order of magnitude. Conclusion Four different polymorphic forms of tiotropium bromide present at 0.4 w/w% concentration in lactose powder blends were unambiguously identified by the synchrotron XRPD method.

A morphology transition from the coexistence of spherical and worm-like mesopores to highly branched wormlike mesopores within the titania thin films has been realized by varying the sol gel reaction time from 51 minutes to 50 hours in the four-component templating system of PS-b-PEO, 1,4-dioxane, concentrated HCl, and Titanium tetraisopropoxide (TTIP). The impact of sol gel reaction time on the local structure, long range lateral structure, and vertical structure of the as-prepared, calcined, and UV degraded thin films, and structure change in solution have been systematically investigated by scanning electron microscopy (SEM), atomic force microscopy (AFM), grazing incidence small angle X-ray scattering (GISAXS), X-ray reflectivity (XRR), and dynamic light scattering (DLS) respectively. With the sol gel reaction time up to 5 hours, the morphology does not change significantly. Both spherical and worm-like domains exist, which are converted to spherical and worm-like mesopores after calcination or UV degradation due to the removal of the PS block. However, with the sol gel reaction time extended to 25 and 50 hours, highly branched worm-like domains appear. As a result, highly porous mesopores are formed by calcination or UV degradation. The GISAXS results prove that the local structure change revealed by AFM and SEM is representative over macroscopic scale. X-ray reflectivity results indicate that an additional thin layer exists beneath the mesoporous titania layer due to the presence of large amount of worm-like domains. Dynamic light scattering (DLS) studies imply that the morphology transition is due to the fusion process of the worm-like micelles in solution.

The aim of this study was to investigate influencing factors on the dissolution test for powders for pulmonary delivery with USP apparatus 2 (paddle apparatus).We investigated the influence of dose collection method, membrane holder type and the presence of surfactants on the dissolution process. Furthermore, we modeled the in vitro dissolution process to identify influencing factors on the dissolution process of inhaled formulations based on the Nernst-Brunner equation.A homogenous distribution of the powder was required to eliminate mass dependent dissolution profiles. This was also found by modeling the dissolution process under ideal conditions. Additionally, it could be shown that influence on the diffusion pathway depends on the solubility of the substance.We demonstrated that the use of 0.02% DPPC in the dissolution media results in the most discriminating and reproducible dissolution profiles. In the model section we demonstrated that the dissolution process depends strongly on saturation solubility and particle size. Under defined assumptions we were able show that the model is predicting the experimental dissolution profiles.

One way of measuring adhesion forces in fine powders is to place the particles on a surface, retract the surface with a high acceleration, and observe their detachment due to their inertia. To induce detachment of micrometer-sized particles, an acceleration in the order of 500,000g is required. We developed a device in which such high acceleration is provided by a Hopkinson bar and measured via laser vibrometry. Using a Hopkinson bar, the fundamental limit of mechanically possible accelerations is reached, since higher values cause material failure. Particle detachment is detected by optical video microscopy. With subsequent automated data evaluation a statistical distribution of adhesion forces is obtained. To validate the method, adhesion forces for ensembles of single polystyrene and silica particles on a polystyrene coated steel surface were measured under ambient conditions. We were able to investigate more than 150 individual particles in one experiment and obtained adhesion values of particles in a diameter range of 3-13 μm. Measured adhesion forces of small particles agreed with values from colloidal probe measurements and theoretical predictions. However, we observe a stronger increase of adhesion for particles with a diameter larger than roughly 7-10 μm. We suggest that this discrepancy is caused by surface roughness and heterogeneity. Large particles adjust and find a stable position on the surface due to their inertia while small particles tend to remain at the position of first contact. The new device will be applicable to study a broad variety of different particle-surface combinations on a routine basis, including strongly cohesive powders like pharmaceutical drugs for treatment of lung diseases.

To evaluate different dissolution testing methods and subsequently develop a simple to perform but reproducible and discriminating dissolution technique for inhalative powders. From a dry powder a fraction of aerosolized particles with an aerodynamic particle size below 5 μm was collected on regenerated cellulose membranes using an abbreviated Andersen cascade impactor. The membrane was then transferred to the respective dissolution set up either paddle apparatus with membrane holder, flow through cell or Franz diffusion cell. All tested dissolution techniques could discriminate between good and poorly soluble substances, but only the paddle apparatus differentiated between small variations of solubility. We showed that membrane coverage and particle diameter play an important role for the dissolution rate. The profiles were fitted with mathematical models (e.g., Weibull, first order) choosing the best fit for determination of the mean dissolution time. Furthermore, a correlation between the dissolution profiles obtained with Franz cell compared to paddle apparatus could be shown. The paddle apparatus with membrane holder has the best discrimination power with optimal reproducibility.

A facile route to reassemble titania nanoparticles within the titania-block copolymer composite films has been developed. The titania nanoparticles templated by the amphiphilic block copolymer of poly(styrene)-block-poly (ethylene oxide) (PS-b-PEO) were frozen in the continuous PS matrix. Upon UV exposure, the PS matrix was partially degraded, allowing the titania nanoparticles to rearrange into chain-like networks exhibiting a closer packing. The local structures of the Titania chain-like networks were investigated by both AFM and SEM; the lateral structures and vertical structures of the films were studied by GISAXS and X-ray reflectivity respectively. Both the image analysis and X-ray scattering characterization prove the reassembly of the titania nanoparticles after UV exposure. The mechanism of the nanoparticle assembly is discussed.

Micron and submicron particles tend to form agglomerates due to adhesive and cohesive forces. The disintegration of these dry powder agglomerates often represents a major task in powder technology. One model describing the mechanical stability of granulates is given by the planar fracture model of Rumpf. In the present work, a new model is introduced intended for applications where a complete disintegration of dry powder agglomerates is required (e.g. for pharmaceutical aerosol generation). Therefore, the breakup of every single connection inside an agglomerate is considered and the dispersion strength σdisp of model agglomerates is calculated and discussed. In order to balance the stability of agglomerates predicted from the model with the stress which is required for powder dispersion, mechanisms of deagglomeration in fluids are discussed. Furthermore it could be shown from an example of a dry powder disperser, that a step-wise disintegration is most likely which can also be described by the model.

The microphase orientation/reorientation alignment kinetics behaviour of lamellar PS-b-PB diblock and PS-b-PB-b-PS triblock copolymers under LAOS conditions is studied. By online monitoring the degree of the mechanical nonlinearity during the orientation process, as determined via the higher harmonics in FT rheology [i.e: I 3/1 (t), ∅ 3 (t)], and investigation of the orientation distribution by 2D-SAXS, the kinetics of the microphase alignment for different experimental shear conditions was followed. For di- and triblock copolymers, the shear orientation into parallel alignment is possible and the kinetics of orientation is strongly dependent on the strain amplitude.

Polymer brush coatings are well-known for their ability to tailor surface properties in a wide range of applications from colloid stabilization to medicine. In most cases, the brushes are used in solution. Consequently, efforts were expended to experimentally investigate or theoretically predict the swelling behavior of the brushes in solvents of different qualities. Here, we show that the micromechanical cantilever (MC) sensor technique is a tool to perform time-resolved physicochemical investigations of thin layers such as polymer brushes. Complementary to scattering techniques, which measure the thickness, the MC sensor technique provides information about changes in the internal pressure of the brushes during a swelling and deswelling process. We show that the kinetics of both swelling and deswelling are dependent on solvent quality. Comparing the measured data with its thickness evolution, which was calculated based on the Flory-Huggins theory, we found that only the first 10% of the thickness increase of the polymer brush results in a significant pressure increase inside the polymer brush layer.

Dynamics and microstructure of the surfactant layer in organically modified silicates and their composites with polystyrene were studied as a function of surfactant loading and temperature in the range relevant for melt intercalation. Site selectivity was achieved by using specifically headgroup- and tail-labeled surfactant EPR spin probes and by applying 31P MAS NMR to phosphonium surfactants. Bimodal dynamics is observed over a broad range of surfactant loadings and temperatures in both the absence and presence of polymers and correlates with a bimodal distribution of surfactant headgroup distances from the silicate surface. Excess surfactant with respect to the cation exchange capacity of the silicate plasticizes the surfactant layer. Electron spin echo envelope modulation on nanocomposites with ammonium surfactant and deuterated polystyrene demonstrates close contact between the polymer and surfactant tail ends. Surfactant dynamics changes strongly during microcomposite formation, i.e., by embedding s...

A technique to cover microelectromechanical systems (MEMS), such as micromechanical cantilever (MC) sensors, with a covalently bound brush layer has been developed. The polymer layer was grown using a grafting-from synthesis of polymer brushes under mild conditions, by surface-initiated atom transfer radical polymerization. Atomic force microscopy (AFM) and ellipsometry have revealed a uniform thickness of about 12 nm from which a graftin density of polymer brushes of 0.19 chains.nm -2 was estimated. The coating with polymer brushes can be realized on a selected surface. It was shown that a single-sided brush layer swells reversibly in toluene, resulting in a bending of the micromechanical cantilever.

The aim of this study was to compare different physical and chemical methods with fluorescence correlation spectroscopy (FCS) in order to characterise cationic acrylate nanoparticles (NP), which can deliver oligonucleotides (ON) into mammalian cells. These positively charged nanoparticles were prepared from diethylaminoethyl dextran (DEAE-dextran) and poly(n-butyl-2-cyanoacrylate) (PBCA). NP consists of PBCA oligochains with an average size of PBCA 9 mer and were formed by entrapping DEAE-dextran and dextran 70,000 in high amounts into the particle matrix. The oligochain length of PBCA was investigated by mass-spectroscopy (MALDI TOF). The molecular weight of a particle with d = 108 nm was estimated to be approximately 3.6 x 10(8) Da. The mean size of the nanoparticles were in a range of dh = 130-140 nm, as determined independently by FCS and dynamic light scattering. Atomic force microscopy and scanning electron microscopy images confirm this size range. Furthermore, the particle mass of the PBCA-NP was estimated by FCS measurements. For this approach two new methods for fluorescence labelling of cationic particles were developed. Fluorescent labelled dextran 70,000 was entrapped into the particle matrix; in addition, the derivatisation of hydroxyl groups of the NP was achieved with 5-([4,6-dichlorotriazin-2-yl]amino) fluorescein (DTAF). ON can be localised in a complex with the NP by dual-colour fluorescence cross correlation spectroscopy measurements. The zetapotential of the unloaded NP was positively charged with about +39 mV and decreased down to -40 mV on addition of excess ON. After centrifugation quantification of the ON loading onto the particles by strong anion exchange high performance liquid chromatography (SAX HPLC) and FCS showed that approximately 20 microg ON per 100 g NP was adsorbed. The FCS measurements of the ON adsorption in situ was found to be much higher with approximately 95 microg ON per 100 g NP.

Structure formation in a multicomponent ultrathin polymer blend film was investigated at and below the surface with grazing incidence X-ray and neutron scattering and scanning force microscopy (SFM). Two films were examined. First a strongly incompatible binary polymer blend film in which a buried structure was clearly identified. This binary blend film then was compared with a ternary blend film into which 5 wt% of a compatibilizing copolymer had been added. The addition of the compatibilizer was found to decrease the size of the internal structures, while leaving the surface morphology unchanged.

Today, a variety of devices for dry powder inhalers (DPIs) is available and many different formulations for optimized deposition in the lung are developed. However, during the production of powder inhalers, processing steps may induce changes to both, the carrier and active pharmaceutical ingredients (APIs). It is well known that standard pharmaceutical operations may lead to structural changes, crystal defects and amorphous regions. Especially operations such as milling, blending and even sieving generate these effects. These disorders may induce re-crystallization and particle size changes post-production which have a huge influence on drug delivery and product stability. In this study, pilot tests with a polar solvent (water) and hydrophilic drug (Salbutamol sulfate) were performed to receive a first impression on further possible implementation of hydrophobic samples with organic solvents. Thereafter, a reliable method for the accurate detection of low amounts of amorphous content is described up to a limit of quantification (LOQ) of 0.5% for a hydrophobic model API (Ciclesonide). The organic vapor sorption method which is a gravimetric method quantifies exactly these low amounts of amorphous content in the hydrophobic powder once the suitable solvent (isopropanol), the correct p/p0 value (0.1) and the exact temperature (25°C) have been found. Afterward it was possible to quantitate low amorphous amounts in jet-milled powders (0.5-17.0%). In summary, the data of the study led to a clearer understanding in what quantity amorphous parts were generated in single production steps and how variable these parts behave to fully crystalline material. Nevertheless it showed how difficult it was to re-crystallize hydrophobic material with water vapor over a short period. For the individual samples it was possible to determine the single humidity at which the material starts to re-crystallize, the behavior against different nonpolar solvents and the calculation of the reduction of the glass transition temperature (Tg) according to the Gordon-Taylor equation.

This article concerns the adsorption of the diblock polyampholyte poly(methacrylic acid)-block-poly((dimethylamino)ethyl metharylate) (PMAA-b-PDMAEMA) from aqueous solution on silicon substrates. The investigated polyampholyte is characterized by a small molecular weight around 15,000 g/mol and a big positively charged PDMAEMA block. The adsorbed amount determined by ellipsometry was strongly influenced by the pH of the adsorption solution. Using dynamic light scattering polyampholytic structures with diameters around 50 nm were found in aqueous solution. The hydrodynamic diameter was hardly affected by changing the pH of the polymer solution. Analogous regular structures were also found by scanning force microscopy (SFM) and grazing incidence, small angle X-ray scattering (GISAXS) at the silicon surface after the adsorption process. While SFM provides a topographical image of a small part of the adsorbed polyampholytic layer, GISAXS was used to get a statistical description of the lateral surface structures. The adsorbed structures were highly regular and their sizes were nearly pH independent over a large pH region. Only directly at the isoelectric point of the polyampholyte larger adsorbed structures were observed. Compared with earlier investigated PMAA-b-PDMAEMA systems we are now able to prepare highly regular polyampholytic structures at silicon surfaces. There are two kinds of interactions for the adsorbed micelles. First, the charged block of the chains is directly attracted to the substrate via electrostatic interactions, while the uncharged part of the chains is only hydrophobically attracted via the hydrophobic core of the adsorbed micelle.

The surface topography and the chemical morphology of poly(styrene-block-paramethylstyrene) diblock copolymers confined within isolated drops are investigated. The drop geometry imposes a two-dimensional spatial restriction. With scanning force microscopy, the film thickness dependence of the mean drop distance as the basic topographical feature is determined. In addition to large drops, a second smaller droplet structure is observed among the drops. The comparison of grazing incidence small-angle scattering using X-rays and neutrons shows that inside the drops the diblock copolymer orients into perpendicular lamellae with respect to the substrate surface. Compared to the bulk, the lamellar spacing is stretched parallel to the substrate.

With specular and off-specular X-ray scattering the surface morphology in terms of surface roughness, film quality, and roughness correlation in thin polymer films of polystyrene and fully brominated polystyrene is measured. During the preparation of the thin films on top of silicon substrates, the common solvent was varied. We investigated eight different solvents and three different solvent mixtures to depict the influence of typical solvent parameters. In the regime of a small solvent vapor pressure, we observed correlated roughness as the ultimate lower limit of accessible surface smoothness. The resulting films are homogeneous, and the surface roughness is given by the substrate. In an intermediate vapor pressure regime marked surface morphologies are detected, while at a high vapor pressure smoother films result again.

A morphology transition from spherical mesopores to worm-shaped mesopores within titania block copolymer composite thin films has been observed by varying the sol–gel reaction time from 40 min to 48 h in the four-component templating system of polystyrene-$\mathit{b}$-poly(ethylene oxide) (PS-$\mathit{b}$-PEO), 1,4-dioxane, concentrated HCl, and titanium tetraisopropoxide (TTIP) with a PS-$\mathit{b}$-PEO mass concentration of 0.25 wt.-%. The impact of the sol–gel reaction time on the local structure, long-range lateral structure, and vertical structure of the as-prepared, calcined, and UV-degraded thin films as well as the structural changes in solution have been systematically investigated by scanning electron microscopy (SEM), atomic force microscopy (AFM), grazing-incidence small-angle X-ray scattering (GISAXS), X-ray reflectivity (XRR), and dynamic light scattering (DLS). With sol–gel reaction times of up to 5 h, hexagonally organized spherical micelles are present within the as-prepared composite films, in which the core of the spherical micelles is composed of the polystyrene (PS) block, and the corona is composed of the poly(ethylene oxide)–titania (PEO–titania) hybrid. Upon calcination or UV exposure, ordered mesoporous structures are formed owing to the removal of the PS block. With the sol–gel reaction time extended to 25 and 48 h, worm-shaped micelles appear, and their quantity increases with increasing sol–gel reaction time. Worm-shaped mesopores are formed by calcination or UV degradation. The GISAXS results prove that the local structural changes are representative over a macroscopic scale. The XRR results suggest that with the sol–gel reaction time extended to 48 h there is an additional thin layer beneath the mesoporous titania layer owing to the presence of a large amount of worm-shaped micelles. The results of the DLS studies imply that the morphology transition from spherical micelles to worm-shaped micelles is caused by a fusion process of the spherical micelles in solution.

Ordered 2D-arrays of TiO 2 nanoparticles were synthesised by a poly(styrene)-block-poly(ethylene oxide) (PS-b-PEO) block-copolymer templated sol–gel process within a thin polymer film. The order within the filled polymer films was found to depend on the sol–gel content during synthesis. Grazing incidence small angle X-ray scattering and scanning electron microscopy imaging proved that well-ordered structures were created over large areas of the thin hybrid film.

A morphology evolution of thin films of titania from spherical mesopores to worm-shaped mesopores was realized by simply varying the sol–gel reaction time from 46 min to 25 h in the quadruple system consisting of polystyrene–block-poly(ethylene oxide) (PS–b-PEO), 1,4-dioxane, concentrated HCl, and titanium tetraisopropoxide (TTIP). Imaging techniques including scanning electron microscopy (SEM) and atomic force microscopy (AFM) were applied to investigate the local structure change of the as-prepared, calcined, and UV-degraded composite films. Grazing incidence small angle X-ray scattering (GISAXS) experiments prove that the structure change in local areas is representative of that over the macroscopic scale. An X-ray reflectivity (XRR) investigation reveals that the vertical structure change happens when the sol–gel reaction is extended from 5 to 25 h. A combination of imaging and scattering techniques provides a powerful tool to elucidate the impact of the sol–gel reaction time on the morphology evolution of the composite films. Dynamic light scattering (DLS) studies imply that the morphology evolution within the films is due to the structure change in solution. A mechanism of the morphology evolution with sol–gel reaction time is proposed on the basis of these results, which provide not only a new way to control the morphology of titania block copolymer composite films but also deep insights into the kinetics of the amphiphilic block copolymer templating process.

The lateral structures of dried adsorbed binary mixtures of star polymers were investigated. Blends of protonated and deuterated polybutadiene stars were prepared from cyclohexane solutions and adsorbed onto silicon substrates. The number of arms and the molecular weight of the arms was varied. With grazing incidence small angle scattering techniques (GISAS) and scanning force microscopy (SFM), different dominant in-plane length scales were determined. The morphology of these structures is dominated by blob-like structures created from single stars or agglomerates of star polymers.

High-density arrays of titania nanoparticles were prepared using a polystyrene-b-poly(ethylene oxide) block copolymer (PS-b-PEO) as a template and a titanium tetraisopropoxide based sol-gel precursor as titania source via a spin-coating method. The hydrophilic titania sol-gel precursor was selectively incorporated into hydrophilic PEO domains of PS-b-PEO and form titania nanoparticle arrays, due to a microphase separation between the PS block and the sol-gel/PEO phase. Field emission scanning electron microscopy (FESEM) and scanning probe microscopy (SPM) images showed that the uniformity and long-range order of the titania/PEO domains improved with increasing sol-gel precursor amount. Grazing incidence small-angle X-ray scattering (GISAXS) results indicate that the ordered structures exist over large length scales. Titania nanocrystal arrays of anatase modification were obtained by calcination at 600 degrees C for 4 h. After calcination, separated particles were observed for low and medium amounts of sol-gel precursors. Films with higher precursor amounts showed wormlike structures due to the aggregation between neighboring particles. Removal of the polymer matrix via UV treatment leads to highly ordered arrays of amorphous titania while retaining the domain size and interparticle distance initially present in the hybrid films. Photoluminescence (PL) properties were investigated for samples before and after calcination. The PL intensity increases with the increasing amount of sol-gel precursor. Bands at 412 nm were ascribed to self-trapped exitons and bands at 461 and 502 nm to oxygen vacancies, respectively. Uncalcined or UV-treated samples also showed PL properties similar to calcined samples, indicating that the local environment of the titanium atoms is similar to the environment of the crystalline anatase modification.

Micromechanical cantilever arrays coated with polymer brushes are an alternative to traditional chemical sensors. A critical parameter for the sensor sensitivity is the coating quality, and small changes in the coating uniformity generate a different behavior of the sensors. Microfocus grazing incidence small-angle x-ray scattering proved to be a sensitive tool to characterize coating quality, enabling a structural and chemical coating analysis.