Pharmaceutical Particles Research Articles

Impact attrition of brittle structured particles at low velocities: rigorous use of a laboratory vibrational impact tester

Brittle particle impact attrition was measured over three orders of magnitude of impact velocity by use of both single- and multiple-impact testers. The multiple-impact tester was a resonant cantilever impactor with dynamic amplitude control and small-gap cavities, designed to ensure operation near the transition between the bouncing and resonant impact regimes. For this impactor, a novel technique using a trajectory simulation was developed to elucidate average impact velocities, effective particle restitution behavior, and average losses per impact from a set of nominal attrition rates (loss/time). This allowed direct comparison of data from the single-impact and multiple-impact testers. Results were obtained for three brittle, porous pharmaceutical particles with significantly-different, well-characterized internal structures. Results reveal a relatively unexplored mode of attrition that is distinguished by lack of gross fragmentation at low velocities, with a steep velocity dependence. This regime is expected for any brittle particle for which simple chipping is not seen—such as rounded solid particles and many agglomerates. At higher impact velocity, gross particle fragmentation is observed. The transition between these attrition regimes appears connected to particle structure, such as the size of attrition-resistant primary particles in an agglomerate or the point at which dominant flaws (that lead to fragmentation) are no longer critically active. The ranking of particles according to damage in high-velocity impacts was not predictive of damage in low-velocity impacts, because the particle attrition did not necessarily exhibit the same velocity-dependence in the two regimes. Such differences are critical for predicting performance in operations such as pneumatic conveying or fluidized beds, respectively.

Crystallization of Paracetamol under Oscillatory Flow Mixing Conditions

There has been an increasing effort in designing pharmaceutical particles with controllable properties (quality) such as chemical purity, morphology, size distribution, surface characteristics, and microstrain content. In this paper, we explore the feasibility of oscillatory flow mixing (OFM) in improving the quality of pharmaceutical precipitates, using paracetamol (4-acetamidophenol) as a model system. In-situ atomic force microscopy (AFM) and optical microscopy were applied to observe the growth of {110} faces of single paracetamol crystals. These studies showed that (a) the bunching and macrostep formation occur at all values of supersaturation; and (b) the oscillation of solution with respect to the growing interface and its relative velocity are the critical parameters for the minimization of the interfacial instabilities, and in turn, for maintaining structural quality. These findings were tested in a conventional impeller driven batch crystallizer (IDBC) and in an oscillatory baffled batch crystallizer (OBBC), in which, apart from hydrodynamics, all external conditions such as initial supersaturation and crystallization temperature were kept constant. The physical properties (the quality) of the precipitates were characterized by low angle laser light scattering (LALLS), scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD), respectively. The analysis of obtained results and their comparison for these two types of mixing shows clearly that particles precipitated in OBBC are of significantly higher quality than those produced in IDBC. A computational fluid dynamics (CFD) software package, Fluent 5, was used to model dynamical fluid patterns in both crystallizers.

Image Analysis of the Shape of Granulated Powder Grains

This study presents and evaluates two new form factors for the characterization of pharmaceutical microparticles using image analysis techniques. The first factor, denoted Vr, is mean percentage variation in radial chord length (for a large number of radial chords drawn at small angular intervals) with respect to mean radial chord length. The second factor, denoted Vp, is percentage deviation of measured perimeter from the perimeter of a circle with radius equal to the mean radial chord length of the particle. Considering both ideal shapes and real pharmaceutical particle populations, these factors are compared with other form factors widely used in pharmaceutical technology. Our results indicate that Vr and Vp allow effective assessment of whether the particles of a given population show pharmaceutically significant deviations from sphericity. The two factors additionally facilitate identification of the basic shapes of particle outlines (notably ellipsoid, rectangular, and irregular). These factors may thus be of value for the characterization and monitoring of pharmaceutical pelleting processes. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association

Adhesion force measurement of a DPI size pharmaceutical particle by colloid probe atomic force microscopy

The method to determine the adhesion characteristics of fine drug particles for dry powder inhalation (DPI) was established using a colloid probe which mounted a 1–3 μm drug particle on a commercial atomic force microscope (AFM) cantilever. A new preparation system of colloid probes for fine particles smaller than 2.5 μm in diameter was developed with the aid of a micromanipulator and a video microscope. Using this colloid probe, adhesion force distribution between a spherical polycrystalline drug particle and a plate of lactose monohydrate representing for DPI carrier materials or stainless steel for device wall materials was measured. Atmospheric humidity as well as the material and surface roughness of a target plate affected the determined adhesion force. With increasing surface roughness of a lactose plate, the adhesion force between a drug particle and the plate distributed more widely and their mean value decreased. Adhesion force increased meaningfully with atmospheric humidity. Adhesion force for stainless steel was higher than that for lactose.

Processing of spherical crystalline particles via a novel solution atomization and crystallization by sonication (SAXS) technique.

The objective was to develop a single-step pharmaceutical particle engineering technique able to produce particles within a well-defined particle size range while controlling macroscopic spherical morphology and mesoscopic surface topography. Paracetamol (acetaminophen) aerosol droplets were generated by spraying a solution via either an electrohydrodynamic atomizer (EHDA) or an air pressure atomizer. The highly supersaturated droplets were collected in a suitable nonsolvent of the drug and crystallized by ultrasonication. Suspended particles were filtered, and their physicochemical properties characterized. The SAXS processed particles showed a relatively homogeneous particle size distribution between 1 and 5 microm. Particles were nominally crystalline in structure. The chemical structure of the active ingredient did not apparently alter during processing. Controlling the solute concentration of the air pressure atomized solution provided a means of controlling the degree of sphericity and particle-size characteristics. In comparison to micronized paracetamol particles, SAXS-produced particulates were generally more uniform in shape with increased nanometer surface roughness. The SAXS process provides a novel means of producing crystalline particles in a well-defined particle size range. Furthermore, the method offers a range of opportunities in controlling physical properties including surface topography and particle shape.

Measurement and Evaluation of the Adhesive Force between Particles by the Direct Separation Method

We developed a new apparatus to measure the adhesive force between particles with a high resolution of approximately 2 nN. The force was measured directly by applying a pulling force to the particles with a contact needle. In addition, the separation process was observed with a 3CCD camera during the measurement. The adhesive force of six kinds of pharmaceutical particles and glass beads was measured, and the effects of moisture, shape, and triboelectrification of the particles on the force were investigated. In the case of moisture‐adsorptive particles, the force of adhesion increased rapidly with moisture content under high relative humidity. In the case of moisture‐nonadsorptive particles, the force was affected by the particle shape and triboelectrification. The adhesive force of particles having sharp corners was greatly affected by triboelectrification at the corners of the particles.

Distinct element analysis of the effect of temperature on the bulk crushing of α-lactose monohydrate

Cryogenic milling could reduce the ductility in the milling operations of semi-brittle and relatively ductile pharmaceutical particles. However, to achieve a better application of this technology, it is necessary to establish the relationship between the influence of temperature on the mechanical properties and breakage characteristics of the single particle and the bulk crushing behavior of these types of material. The focus of this paper is on the analysis of bulk crushing behavior of α-lactose monohydrate particles in response to temperature variations, based on single particle mechanical properties and side crushing strength at different temperatures and the use of distinct element analysis. The effect of temperature on the side crushing strength of the particles has been quantified by quasistatic side crushing tests. The experimental results show a significant increase in the strength of the single particles by decreasing the temperature. These results are used in the distinct element analysis to simulate the bulk crushing behavior of pharmaceutical particles as affected by the temperature. The predictions are compared with the experimental results, for which a reasonable agreement is found for the ambient temperature case. There are some differences for the case of −20°C, due to lack of reliable data for Young's modulus.

Measurement of pharmaceutical particles using a time-of-flight particle sizer

The Aerosizer ® is an instrument for time-of-flight measurement, which is widely used in particle size determinations. The results of various studies indicate that there are still some problems related to the optimization of the analysis conditions. In this study, the behaviour of a set of different kinds of pharmaceutical particles during Aerosizer measurements was studied. An Aerosizer LD equipment with an Aero-Disperser™ was validated with particle size standards. Volume particle size distributions of particles with different size and shape characteristics were determined (PVP, Celphere ®, lactose, a drug substance, PHB microparticles). The aim was to investigate the effects of the shear force and deagglomeration levels during the dispersion of the particles on the particle size distributions that were obtained. The results of this study indicate that the ability of the instrument to disperse particles is highly dependent on the properties of the materials. According to the validation measurements, the instrument gives accurate results for spherical, uncohesive particles. The capability of the dispersing unit to separate particles aerodynamically was well observed with PVP. Time-of-flight measurements were uncomplicated for relatively large particles, such as Celphere ®, which have little interaction with each other and with the instrument housing. For lactose, increasing shear force rates resulted in size distributions with larger particle sizes. In the case of the PHB microparticles the results indicated that the aggregates became smaller and particles were partly separated to primary particles with all shear force levels.

Pull-off Force Measurements between Rough Surfaces by Atomic Force Microscopy

Direct measurements of the pull-off (adhesion) forces between pharmaceutical particles (beclomethasone dipropionate, a peptide-type material, and lactose) with irregular geometry and rough polymeric surfaces (series of polypropylene coatings, polycarbonate, and acrylonitrile-butadiene-styrene) were carried out using the atomic force microscope. These measurements showed that roughness of the interacting surfaces is the significant factor affecting experimentally measured pull-off forces. A broad distribution of pull-off force values was noted in the measurements, caused by a varying adhesive contact area for a particle located on rough substrate. The possibility of multiple points of contact between irregularly shaped pharmaceutical particles and substrate surfaces is demonstrated with nanoindentations of the particle in a fluoro-polymer film. Force–distance curves showing the “sawtooth” pattern are additional evidence that particles make contact with substrates at more than one point. Reduced adhesion of 10- to 14-μm-diameter lactose and peptide material particles to the polypropylene coatings with a roughness of 194 nm was found in this study. Similar pull-off force versus roughness relationships are also reported for the model spherical particles, silanized glass particle with a size of 10 μm and polystyrene particle with a diameter of 9 μm, in contact with polypropylene coatings of varying roughness characteristics. It was found that the model recently proposed by Rabinovich et al. (J. Colloid Interface Sci. 232, 1–16 (2000)) closely predicts the pull-off forces for glass and lactose particles. On the other hand, the adhesion of the peptide material and polystyrene particle to polypropylene is underestimated by about an order of magnitude with the theoretical model, in which the interacting substrates are treated as rigid materials. The underestimate is attributed to the deformation of the peptide material and polystyrene particles.

Analysis of the drying process of seed particles in a spouted bed with a draft tube

Although a spouted bed with a draft tube is widely used in pharmaceutical particle coating to modify the release characteristics of various medicines, the coating conditions and pharmaceutical formulations are determined mostly based on experience and experiments. In the present work, we theoretically analyzed the drying process of particles by applying a cell model, which is defined as an average air volume occupied by a single seed particle. We established material balance and heat balance equations in the cell, and analyzed the drying process using evaporation flux measured by experiments. Furthermore, experiments were carried out to measure the drying process of seed particles in laboratory-scale equipment. As a result, it was found that calculated tendencies of increasing or decreasing water content of seed particles are in good agreement with the experimental data. The parameters controlling the drying process of seed particles were derived by the present analysis and the influences of these parameters discussed.

Adhesion of pharmaceutical particles to gelatin capsules having variable surface physicochemical properties: evaluation using a combination of scanning probe microscopy techniques

The adhesion of particles to solid surfaces is an important factor in the performance of a number of technologically significant systems. A combination of scanning probe microscopy (SPM) techniques, including adhesion mapping and force integration to equal limits imaging, is used to correlate the adhesion of particles with areas of distinct surface physicochemical properties. The utility of this approach is demonstrated using lactose particles and a gelatin capsule from a pharmaceutical dry powder inhalant drug delivery system. The particle adhesion forces were found to be higher on specific domains of the gelatin capsule identified as extraneous surface contamination. Furthermore, the dynamic nature of these contaminant domains on the capsule surface was found to result in a variance in the particle adhesion over time.

Characterisation of adhesional properties of lactose carriers using atomic force microscopy.

The atomic force microscopy (AFM) colloid probe technique was investigated as a method for the characterisation of adhesional properties of pharmaceutical powder surfaces. Lactose carriers used in dry powder inhaler (DPI) formulations were chosen for investigation since adhesion between the carrier surface and drug particles has been proposed to affect the dispersion of drug particles. Individual adhesion forces were determined by measuring the detachment forces in air between the colloid probe and the lactose particle surface. The colloid probe consisted of a silica sphere (10 microm diameter) attached to a V-shaped silicon nitride cantilever (spring constant, k=0.42 N/m). Adhesion forces were calculated from individual force-distance curves using Hooke's Law. Individual forces measured at various adhesion sites were observed to be reproducible and stable over 10 min (coefficient of variation, CV below 5%). The adhesion force distribution determined from measurements at multiple sites (n>50) on each sample followed a log-normal relationship (regression coefficient, r(2) ranged between 0.95 and 0.99). This enabled characterisation in terms of the geometric mean adhesion force and a geometric standard deviation (GSD). Significant differences (P<0.001) in adhesion force were observed between samples, ranging from 37.47+/-1.95 to 117.48+/-2.20 nN. This study demonstrates the suitability of AFM as sensitive technique for the characterisation of adhesional properties of pharmaceutical particles.

ドラフトチューブ付き噴流層による粒子のコーティング 粒子循環量の制御

ドラフトチューブ付き噴流層による粒子のコーティング 粒子循環量の制御

Direct adhesion measurements of pharmaceutical particles to gelatin capsule surfaces

Scanning probe microscopy (SPM) was used to measure directly the adhesion of individual lactose particles to the surface of gelatin capsules employed in dry powder inhalant drug delivery systems. In this study, SPM shows that gelatin capsule surfaces with high surface heterogeneity and high-contrast friction exhibit high adhesion and that gelatin capsule surfaces with low surface heterogeneity and low-contrast friction exhibit low adhesion. The adhesion of lactose particles to gelatin capsules was also determined by measuring the retention of lactose particles in the capsules. The adhesion trend obtained with individual lactose particles using the colloidal probe technique agrees with the macroscopic retention results. The adhesion appears to be proportional to the particle size for homogeneous capsule surfaces. In dry powder inhalation products, the Lifshitz-van der Waals forces and acid-base interactions appear to be the principal forces contributing to particle-surface adhesion. The physicochemical nature of the capsule surface seems to dictate the spatial variation of adhesion across the surface. The SPM results clearly show that the surface physicochemical properties depend on the gelatin and mold release agent utilized in the manufacture of gelatin capsules. One of the practical implications of this study is that extraneous surface contamination of gelatin capsules by chemical processing aids such as mold release agents appears to be a key factor affecting the respirable fraction in dry powder inhalation products.

ドラフトチューブ付き噴流層による粒子コーティング 操作条件のミスト付着効率への影響

Although spouted bed with a draft tube is widely used in pharmaceutical particle coating to modify the release characteristics of various medicines, the coating condition and pharmaceutical formulation are determined based mostly on experiences and experiments. In the present work, we theoretically analyzed the coating process of a spouted bed with a draft tube by calculating particle trajectories in the draft tube and impaction efficiencies of sprayed mists onto a particle and obtained the coating efficiency. Furthermore, experiments were carried out to measure the coating efficiencies in a laboratory model of spouted bed. As a result, it was found that the number of seed particles in the draft tube was the most important parameter in determining the coating efficiency, suggesting that the coating efficiency can be raised by increasing the number concentration of seed particles.

Fractal analysis of pharmaceutical particles by atomic force microscopy.

Reliable methods are needed to characterize the surface roughness of pharmaceutical solid particles for quality control and for finding the correlations with other properties. In this study, we used fractal analysis to describe the surface roughness. Atomic force microscopy (AFM) was used to obtain three-dimensional surface profiles. The variation method was used to calculate fractal dimensions. We have measured fractal dimensions of four granule samples, four powders, and two freeze-dried powders. A computer-program was written to implement the variation method. The implementation was verified using the model surfaces generated by fractional Brownian motion. The fractal dimensions of most particles and granules were between 2.1 and 2.2, and were independent of the scan size we measured. The freeze-dried samples, however showed wide variation in the values of fractal dimension, which were dependent on the scan size. As scan size increased, the fractal dimension also increased up to 2.5. Fractal analysis can be used to describe surface roughness of pharmaceutical particles. The variation method allows calculation of reliable fractal dimensions of surface profiles obtained by AFM. Careful analysis is required for the estimation of fractal dimension, since the estimates are dependent on the algorithm and the digitized model size (i.e., number of data points of the measured surface profile) used. The fractal dimension of pharmaceutical materials is also a function of the observation scale i.e., the scan size) used in the profile measurement. The multi-fractal features and the scale-dependency of fractal dimension result from the artificial processes controlling the surface morphology.