Fridrun Podczeck

The influence of particle size and shape on the angle of internal friction and the flow factor of unlubricated and lubricated powders

The shear properties of 8 different powders, which varied in particle size and shape, were studied using an annular shear cell. The angle of internal friction and the flow factor were determined. Magnesium stearate was added in concentrations between 0.25 and 1.25% w/w, and the change in the shear properties was recorded. For the unlubricated powders, the angle of internal friction was found to depend both on particle size and shape in a nonlinear manner, whereas the flow factor depended only on particle shape. The optimal magnesium stearate content, i.e. the concentration which gave the lowest angle of internal friction, varied for the powders. Both the angle of internal friction and the corresponding concentration of magnesium stearate depended only on particle shape. A large value for the aspect ratio as obtained for needle shaped particles was accompanied by a particularly high angle of internal friction. The optimal magnesium stearate concentration was least for needle shaped or round particles. The optimal magnesium stearate contents for the flow factor, i.e. the concentrations which gave the highest values of flow factor, were partly different from those obtained for the angle of internal friction. While the flow factor depended only on particle shape, the corresponding optimal magnesium stearate concentration was found to depend only on the particle size. For powders of comparable chemical composition such as maize starch and starch 1500, or microcrystalline and microfine cellulose, the angle of internal friction at an optimal lubricant concentration was found to be proportional to the elastic properties of the powders.

The relationship between physical properties of lactose monohydrate and the aerodynamic behaviour of adhered drug particles

The influence of particle size, shape, particle surface roughness and water loss on drying of lactose monohydrate carrier particles on the aerodynamic properties of dry powder inhalations based on interactive mixtures with a micronized drug has been investigated. Two sets of mixtures were prepared to relate the physical properties of the lactose monohydrate particles to the aerodynamic properties of the formulations: (A) constant mixing time and speed (25 min, 42 rev./min), and (B) optimal mixing time (speed 42 rev./min) to obtain a given adhesion force between drug and carrier particles. All ten lactose monohydrate batches provided different aerodynamic properties under test conditions (A) and (B). The relationship between the physical properties of the lactose monohydrate carrier particles and the aerodynamic properties of the drug is complex, and a simple interchange of the carrier material in terms of brand or grade appears impossible. Particle size, shape, water loss on drying, and to a lesser extent surface roughness influence the loss of drug for example in the device, preseparator and loss due to adhesion. The relationships can be quantified mathematically, if mixing has been undertaken under similar conditions, i.e. identical mixing time and speed (test condition (A)). However, for interactive mixtures, which have been manufactured under test condition (B), the connection between the physical properties of the carrier materials and the aerodynamic behaviour are less quantifiable. A similar adhesion force does not guarantee a similar aerodynamic behaviour of the drug in the cascade impactor. The findings indicate that it is mainly the site of adhesion, i.e. adhesion to fine or larger carrier particles which determines the drug lost in the device and preseparator, and is responsible for deviations in the MMAD.

A shape factor to characterize the quality of spheroids

Abstract— A shape factor eR has been devised to describe how the form of spherical particles approaches that of a true spheroid, based on a two‐dimensional image analysis. Both the deviation of shape from a circle towards an ellipse and surface irregularities influence the value of eR. Using a set of model figures such as squares, triangles, diamonds and stars, it could be shown that eR clearly differentiates between different polygonally symmetric figures, even in the case where common shape descriptors such as the aspect ratio provide equal values. The value of eR is 1·0 in the case of a perfect spheroid, while ellipticity and surface roughness lead to a significant change in the value.

Factors influencing the physical characteristics of pellets obtained by extrusion-spheronization

The objective of this work was to analyse the influence of the solubility of the drug and the filler on the physical characteristics of pellets prepared by extrusion/spheronization. Different formulations were prepared according to a statistical plan, using five different drugs and five different fillers selected according to their water solubility. The pellets were then obtained by a standardized extrusion/spheronization process and evaluated in terms of their physical characteristics by measuring the pellet size, density, porosity, mechanical strength, residual moisture after drying and shape. The results were first analysed by the analysis of variance to identify the main factors involved. The results were further assessed by canonical analysis and the significant influence factors were quantified in terms of regression equations. It can be concluded that the solubility of materials used (both drugs and fillers) plays an important role in the quantity of water required to form satisfactory pellets and on the physical characteristics of pellets. Quantitative relationships were identified between (a) the extrusion force required to provide extrudate, which would form pellets and the natural log of the filler solubility; (b) the quantity of the pellets in the size range 1-1.4 and the solubility of both the filler and the drug; (c) the apparent pellet density and both the level of drug and filler plus the solubility of the filler; (d) the pellet porosity and the quantity of drug and the inverse function of the filler solubility; and (e) the mechanical strength of the pellets and the square root of the quantity of drug.

Preparation of extruded carbamazepine and PEG 4000 as a potential rapid release dosage form.

The aim of this research was to use a ram extruder to prepare directly a fast release dosage form with uniform shape and density, containing carbamazepine (C) as a water-insoluble drug and polyethylene glycol 4000 (PEG) as a low melting binder. The potential inclusion of lactose (L) as a hydrophilic filler was also considered. The temperature suitable to ensure a successful extrusion process of several formulations containing PEG in different percentages was found to be below the melting point of the PEG. The influence of composition on the extrusion process of different ram speeds was checked by measuring the pressure at the steady state, the apparent shear rate and the apparent shear stress of a range of mixtures of drug, lactose and PEG. The physical-mechanical properties of extrudates, including tensile strength and Youngs modulus, prepared with different ram velocities were also determined. The solid-state physical structure by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) was established. The dissolution of the extrudates and their corresponding physical mixtures were compared. The mixtures were found to be shear thinning when extruded; the tensile strength of extrudates was dependent on the composition but not the extrusion rate, while the value of Youngs modulus was strongly influenced by the rate of extrusion, but less affected by the composition of the extrudates. The results of DSC and XRD indicated that the solid structure of the extrudates corresponded to that of a physical mixture of the components, hence there had been no change in the physical form of the drug induced by extrusion. In terms of dissolution, the rate of the extrusion process did not influence the performance of the products, whereas the composition did. The extruded mixtures of an equivalent composition exhibited a more rapid release than a simple physical mixture. The addition of lactose reduced the dissolution rate.

The influence of water content and drug solubility on the formulation of pellets by extrusion and spheronisation

The influence of drug solubility in the range 14.3-1000 gl-1 on the formation of pellets by extrusion and spheronisation has been investigated by evaluating the performance of a series of model drugs mixed with an equal part by weight of microcrystalline cellulose. The optimum formulation in terms of pellet roundness and the maximum quantity within a limited size range was established by preparing samples with a range of water levels. The range of water levels over which pellets could be formed was found to be dependent on the model drug and its particle size. In general the force necessary to extrude the wet mass through the ram extruder was found to decrease as the quantity of water added increased. The optimum water level required to form the best quality pellets was found to decrease as a linear function of the natural logarithm of the water solubility of the drug. If allowance is made for the loss of solid by dissolution of the drug, there is an increase in the apparent water content necessary to form good spheres above a critical solubility between 350 and 400 gl-1.

Influence of Polyethylene Glycol 400 on the Gastrointestinal Absorption of Ranitidine

AbstractPurpose. To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract. Methods. Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-111 to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration. Results. The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and Cmax parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400. Conclusions. These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.

The influence of pellet shape and film coating on the filling of pellets into hard shell capsules

Pellets of different shape, varying from spherical to cylindrical, were filled into hard shell capsules. When no film coat was applied, the pellets had not to be perfectly spherical in order to be filled reproducibly. An aspect ratio of 1.2 or less appeared to be the threshold value. However, pronounced surface roughness hindered the filling process, and hence it appears necessary to monitor this parameter. After coating of the pellets with an ethylcellulose film, none of the batches could be filled to an acceptable standard, because electrostatic loading led to a blockage of the filling mechanism. However, the addition of 1% talcum powder was sufficient to remove all charges, and again filling became a function of the pellet shape, confirming the threshold aspect ratio value of 1.2.

The effect of an increase in chain length on the mechanical properties of polyethylene glycols

The mechanical properties of different molecular weights of polyethylene glycol (PEG) have been determined by formation of compacted tablets and beams, which were subjected to diametral compression and 3-point bending, respectively. From diametral compression, the tensile strength for the different grades of PEG was determined. Flat beams made from powder by compaction were used to determine Youngs modulus of elasticity. Beams into which a notch had been introduced after formation allowed the fracture mechanical parameters of critical stress intensity factor, K(IC), and fracture toughness, R, to be determined. Evaluation of these parameters as a function of compact porosity allowed extrapolation to values at zero porosity, providing an estimate of the material properties. The increase in chain length of the PEG was found to have a non-linear effect on tensile strength and Youngs modulus. The ductility of the polymer increased proportionally to the increase in chain length, reflected by the linear relationship between K(IC) and the molecular weight. Youngs modulus and critical stress intensity factor allowed the estimation of the strain energy release rate, G(IC), which is the driving force in crack propagation. Consequently, the tensile strength at zero porosity was found to be predictable from the values of G(IC) and the molecular weight of the different grades of PEG.

The influence of particle size and shape of components of binary powder mixtures on the maximum volume reduction due to packing

The influence of particle size and shape of components of binary powder mixtures on the maximum volume reduction due to packing has been investigated in a systematic manner using the Kawakita-equation. Different grades of microcrystalline cellulose were mixed with defined size fractions of angular particles (lactose monohydrate), spherical particles (Elcema G250) and needle-shaped particles (acetylsalicylic acid). The particle shape of the mixture components clearly influenced the maximum volume reduction due to packing, represented by the Kawakita constant a. While angular particles improved the packing properties of the microcrystalline celluloses, the addition of spherical and needle-shaped particles generally resulted in lower values for a at equivalent concentrations. The addition of both spherical or needle-shaped particles in concentrations between 25% and 75% to fine grade microcrystalline cellulose led to a steady decrease in volume reduction ability, whereas for medium or coarse grade microcrystalline cellulose the graphical presentation of a as a function of concentration of the second mixture component always showed a maximum value. The particle size of both powders contained in the binary mixtures influenced the values of the Kawakita constant a with the exception of angular particles. The finer the particle size of each component, the larger became the value of a.