Dissolution testing of powders for inhalation: influence of particle deposition and modeling of dissolution profiles.

PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Measuring adhesion forces in powder collectives by inertial detachment.

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.

Dissolution techniques for in vitro testing of dry powders for inhalation.

PURPOSE: To evaluate different dissolution testing methods and subsequently develop a simple to perform but reproducible and discriminating dissolution technique for inhalative powders. METHODS: 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. RESULTS: 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. CONCLUSION: The paddle apparatus with membrane holder has the best discrimination power with optimal reproducibility.

A facile route to reassemble titania nanoparticles into ordered chain-like networks on substrate.

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.

Effect of Unintentional Storage and Handling Errors of Inhaled Medications: What Does This Mean for Therapeutic Equivalence Considerations?

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.

Identification of Polymorphic Forms of Active Pharmaceutical Ingredient in Low-Concentration Dry Powder Formulations by Synchrotron X-Ray Powder Diffraction.

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.

Measurement of low amounts of amorphous content in hydrophobic active pharmaceutical ingredients with dynamic organic vapor sorption.

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.

Physicochemical characterisation of cationic polybutylcyanoacrylate-nanoparticles by fluorescence correlation spectroscopy.

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.

Micromechanical cantilever technique: a tool for investigating the swelling of polymer brushes.

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.

Synthesis and photoluminescence of titania nanoparticle arrays templated by block-copolymer thin films.

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.