Henrik Ehlers

Improving flow properties of ibuprofen by fluidized bed particle thin-coating.

The surfaces of ibuprofen particles (d(50) 42 microm) were modified by coating the particles with diluted aqueous hydroxypropyl methylcellulose (HPMC) solution in an instrumentated top-spray fluid bed granulator. The objective was to evaluate whether an extremely thin polymer coating could be an alternative to granulation in enhancing powder flow and processing properties. The studied variables were inlet air temperature and spray rate. The treated powders showed a clear improvement in flow rate as measured with a flow meter designed for powders with poor flow properties. The particle size was determined using optical microscopy and image analysis. The particle size, size distribution and circularity of the treated and untreated ibuprofen batches showed no difference from each other. Consequently, the improvement in flow properties can be attributed to the trace amounts of hydroxypropyl methylcellulose applied onto the particle surfaces. In conclusion, fluidized bed particle thin-coating (PTC) alters the surface of ibuprofen powder particles and improves the flow properties of ibuprofen powder with changes in neither particle size, size distribution nor morphology.

Granule size control and targeting in pulsed spray fluid bed granulation

The primary aim of the study was to investigate the effects of pulsed liquid feed on granule size. The secondary aim was to increase knowledge of this technique in granule size targeting. Pulsed liquid feed refers to the pump changing between on- and off-positions in sequences, called duty cycles. One duty cycle consists of one on- and off-period. The study was performed with a laboratory-scale top-spray fluid bed granulator with duty cycle length and atomization pressure as studied variables. The liquid feed rate, amount and inlet air temperature were constant. The granules were small, indicating that the powder has only undergone ordered mixing, nucleation and early growth. The effect of atomizing pressure on granule size depends on inlet air relative humidity, with premature binder evaporation as a reason. The duty cycle length was of critical importance to the end product attributes, by defining the extent of intermittent drying and rewetting. By varying only the duty cycle length, it was possible to control granule nucleation and growth, with a wider granule size target range in increased relative humidity. The present study confirms that pulsed liquid feed in fluid bed granulation is a useful tool in end product particle size targeting.

In situ droplet size and speed determination in a fluid-bed granulator.

The droplet size affects the final product in fluid-bed granulation and coating. In the present study, spray characteristics of aqueous granulation liquid (purified water) were determined in situ in a fluid-bed granulator. Droplets were produced by a pneumatic nozzle. Diode laser stroboscopy (DLS) was used for droplet detection and particle tracking velocimetry (PTV) was used for determination of droplet size and speed. Increased atomization pressure decreased the droplet size and the effect was most strongly visible in the 90% size fractile. The droplets seemed to undergo coalescence after which only slight evaporation occurred. Furthermore, the droplets were subjected to a strong turbulence at the event of atomization, after which the turbulence reached a minimum value in the lower halve of the chamber. The turbulence increased as speed and droplet size decreased due to the effects of the fluidizing air. The DLS and PTV system used was found to be a useful and rapid tool in determining spray characteristics and in monitoring and predicting nozzle performance.

Thin-coating as an alternative approach to improve flow properties of ibuprofen powder

In the present study, thin-coating as a potential method for improving flow properties of cohesive ibuprofen powder was introduced. Briefly, the technique was based on the successive deposition of ultrasound-assisted fine polymer mist onto the surface of the powdered active pharmaceutical ingredient (API), producing individual particles with a hydrophilic thin-coat. A 0.15% m/V aqueous solution of hydroxypropyl methylcellulose (HPMC) was used. Particle size and surface analysis revealed a decrease in the cohesiveness of ibuprofen powder and an increase in the homogeneity of particle surfaces as a result of polymer treatment. Superficial changes caused a substantial improvement on the flowing characteristics of coated substance over uncoated. The enhancement in flow rate proceeded as the uniformity of the HPMC layer increased. In conclusion, the proposed technique is a simple and effective method that can be used as a continuous process to modify API particle surface properties, which in turn improve the handling of poorly flowable powder.

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.

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

&NA; 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 &agr;‐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. Graphical abstract Figure. No caption available.

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.

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.

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.

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 Youngs 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 Youngs modulus. The relative standard deviation of 10 consecutive measurements was 3.6%. The results indicate a direct correlation between crushing strength and Youngs modulus, which found further support when comparing surface roughness data and radial recovery of the tablets to Youngs 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.