Investigations into the reduction of powder adhesion to stainless steel surfaces by surface modification to aid capsule filling

The adhesion force of powder particles to stainless steel surfaces, which had been modified by various metal coatings, has been measured using a centrifuge technique. The surfaces were characterised by surface roughness and surface free energy measurements, whereas the particles, which had a particle size of 32-45 microns, were characterised by their surface free energy only. The roughness of the surfaces was found to be similar, so that changes in the adhesion properties of the powders to these surfaces could not be due to a change in this surface property. However, there was a major difference in the surface free energy parameters of the surfaces. The surface free energy varied from a nearly non-polar character to strong Lewis-base. The adhesion force of pregelatinised starch and lactose monohydrate particles increased with the increasing base character of the surfaces. In principle this behaviour could also be seen for calcium carbonate particles. However, here the order of the adhesion forces to the surfaces tested was disrupted on one occasion because of a pronounced influence of particle and surface hardness on this property. In general, the ranking of the adhesion forces matched observations made during capsule filling on a Bosch GKF-400 tamp-filling machine. It was therefore concluded that a metal coating of the tamping pins would be able to reduce powder adhesion. In order to identify the best coating, centrifugal adhesion force measurements could be undertaken, or surface free energy measurements could be made. The results found suggest that a surface finish by means of chromium nitride coating provided, in most cases, a significant reduction of the powder adhesion. For very hard powder particles such as inorganic excipients the hardness of the surfaces must also be increased. In these cases plasma-coating of chromium appears helpful.     

The influence of chitosan and sodium alginate and formulation variables on the formation and drug release from pellets prepared by extrusion/spheronisation

The influence of the incorporation of two oppositely charged hydrophilic natural polymers, chitosan and sodium alginate, alone and in combination, on the ability of formulations containing a model drug (paracetamol) to form spherical pellets by the process of extrusion/spheronisation and the properties of the pellets, has been undertaken. A statistically experimental design was employed to allow the major factors which determined the properties of the pellets, to be identified. A standardised procedure was used to prepare the pellets with a ram producing the extrudate for spheronisation. Statistical analysis of the results indicated that the formulation variables of the type and level of the polymer, the proportion of the model drug, and the proportion of the microcrystalline cellulose influenced (a) the quantity of liquid binder required to produce a good formulation (narrow size range and high value for the shape factor indicating sphericity), (b) the steady-state extrusion force, (c) the pellet perimeter, (d) the apparent pellet density and (e) the porosity of the pellets. The median size of the pellets of the "good formulation" could only be related to the chitosan and sodium alginate content of the formulations. The proportion of the drug, chitosan and sodium alginate content of the formulation significantly influenced the in vitro dissolution of the model drug (paracetamol). The drug release mechanism differed with the formulation variables, although if the pellets remained intact during the dissolution test, diffusion was the controlling mechanism. There was no significant advantage to be gained by using a mixture of the two polymers in terms of retarding drug release.     

The formation of colonic digestible films of amylose and ethylcellulose from aqueous dispersions at temperatures below 37 degrees C.

The film forming properties of a commercial aqueous ethylcellulose dispersion (Surelease) mixed with a range of ratios of an amylose/butanol complex in the presence of a range of concentrations of a plasticiser has been studied by measuring the minimum film forming temperature (MFFT). Contrary to what was to be anticipated from the literature, it was found that an additional 4% of the plasticiser (dibutyl sebacate), normally present in the standard formulation of the ethyl cellulose dispersion, was sufficient to lower the MFFT to allow the formation of films at 35 degrees C. This was confirmed by assessment of the glass transition temperature of free films prepared by casting and drying at 35 degrees C by the application of dynamic mechanical analysis. This technique also demonstrated that the ethylycellulose and the amylose were not miscible. The ability of faecal slurry to digest the films formed at low temperatures was confirmed by the use of a batch fermenter. The extent of digestion was directly related to the amylose content of the films, ensuring the potential to provide films, which could function as colon specific coatings.     

Observations of the clinical characteristics of patients with ventricular tachyarrhythmias--l978 to l985

To get some insight into the clinical profile of patients with ventricular tachyarrhythmias and to elucidate potential time-dependent changes, data from 421 patients with documented tachyarrhythmias referred for electrophysiologic studies, were analyzed. The observation period is extended from 1978 to 1986. Patient's data were analyzed in 2-year subperiods. There were no major changes with regard to underlying heart disease, or within the interval between myocardial infarction and electrophysiologic study, or with regard to the indication for electrophysiologic study and the results of right ventricular stimulation during the analyzed subperiods. The interval between the first episode of documented tachyarrhythmia and the study, as well as the number of previous episodes of documented arrhythmias, decreased significantly between the first observation period (1978/79) and all the following periods. Before 1982, about 2% of patients were on amiodarone therapy at the time of referral, whereas from 1982 a higher proportion of cases was referred on amiodarone (21%, 12%, resp.). Over the whole observation period, an increasing number of patients finally underwent antitachycardia surgery.     

Possibilities and limitations of catheter ablation of tachycardia arrhythmia

Catheter ablation has become an alternative to other non-pharmacological forms of antiarrhythmic therapy. Since supraventricular arrhythmias were first treated by ablation of the AV-conduction system, the clinical use of the technique has recently been extended to treat accessory pathways or ventricular tachycardias. The results of experiences from a number of clinical centers are available. To improve clinical applicability and to avoid complications, besides direct-current ablation, new technologies have been tested experimentally and in some cases already applied to patients. Whereas catheter ablation with radio-frequency alternating current has already been used in patients, the application of laser technology to ablation of arrhythmogenic myocardium has been limited to open heart surgery. Both techniques may offer improvements regarding precision and safety aspects of the method. To perform catheter ablation, a multitude of prerequisites concerning organisatory and safety aspects has to be fulfilled. Thus far, catheter ablation should only be performed in clinical centers with the facilities for cardiac surgery.     

The preparation of pellets containing a surfactant or a mixture of mono- and di-gylcerides by extrusion/spheronization.

The ability to incorporate either of the two components of a self-emulsifying system (polysorbate 80 (PSG80) and a mixture of mono- and di-glycerides (MDG)) separately into pellets prepared by extrusion/spheronization and the properties of any resulting pellets has been investigated. The results have established that it is possible to prepare satisfactory pellets thus adding to the range of ingredients that can be included in pellet formulations. For PS80, it was found possible to prepare pellets containing at least 92% of the surfactant/water mixture, but with a mixture of (MDG) and water, however, it was not possible to prepare pellets, which contained more than 46% of MDG. By analysis of variance significant relationships were established between the ratio of lactose to MCC and the ratio of the PS80 or MDG to water and the properties of the pellets. There were both similarities and differences of the two input factors, which provided relationships for the two materials. The quantity of liquid required, the fluid content of the pellets, the tensile strength and porosity of the pellets provided relationships for both systems, whereas the extrusion force and the median pellet size gave relationships for the PS80 systems, but they did not for the MDG systems. The opposite was true for interquartile range (IQR), the yield in the modal fraction and the shape factor. It was possible to identify global relationships for these systems and those reported previously, when the two components were combined as a self-emulsifying system, by the application of perceptual mapping. It was found that, there were relationships between the size range, expressed as the IQR and the fluid level required to make pellets; the quantity of the non-aqueous component of the fluid and the pellet shape factor; the extrusion force and the tensile strength of the pellets and the yield in the modal fraction and the ratio of the non-aqueous to aqueous content of the fluid used to prepare the pellets. The ability to use the materials independently offers further alternatives for the formulation of water insoluble drugs into pellet formulations.     

The strength of bilayered tablets

The tensile strength of model materials (dicalcium phosphate dihydrate, microcrystalline cellulose and pregelatinised starch) compacted to form tablets in the form of beams consisting of two layers of equal thickness has been determined by three-point loading. The values of the tensile strength of the materials were sometimes higher and sometimes lower than the tensile strength of beams of the same thickness composed of a single material. Correction of the values for the tensile strength of the layered beams for the differences in the elasticity of the materials in the layered tablets failed to correct for these differences, as did considering the layered beams as beams of half thickness. For a layered tablet with pregelatinised starch at the bottom and microcrystalline cellulose at the top, the value of the tensile strength recorded appeared to be that of the microcrystalline cellulose as the fracture propagated across the boundary between the layers and into microcrystalline cellulose. What appeared to be the important factor was the way the failure of the beam crossed the interface between the two layers.     

The influence of pellet shape and surface properties on the drug release from uncoated and coated pellets

The crystallisation of amorphous salbutamol sulphate prepared by spray drying was monitored using a humidity controlled microbalance (Dynamic Vapour Sorption apparatus, Surface Measurement Systems) combined with a near-infrared probe. Amorphous salbutamol sulphate was prepared by spray drying from a solution in water. The particles were then analysed using scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, isothermal microcalorimetry and water vapour sorption analysis combined with near-infrared spectroscopy (NIR). Isothermal microcalorimetry and water vapour sorption combined with NIR spectroscopy were able to detect the transition from the amorphous to crystalline state. However while the isothermal microcalorimeter showed only a classic crystallisation exotherm when the material was exposed at 75% RH, the DVS-NIR results at the same humidity highlighted a more complex process. When exposed at 75% RH, the uptake of water was followed by crystallisation that was detected using NIR. The expulsion of water after crystallisation was very slow and at a constant rate whether the material was exposed to 75 or 0% RH. The NIR and DVS studies indicated that the material had crystallised very soon after exposure to high RH. The water that was expelled during crystallisation was not displaced from the particles and remained associated with the particles for many days. This study showed that the use of gravimetric analysis together with NIR spectroscopy provided valuable information on the dynamics of the crystallisation of salbutamol sulphate. The retention of water within recently crystallised salbutamol is potentially important to the behaviour of dosage forms containing the amorphous (or partially amorphous) form of this drug.     

Determination of the gastric emptying of solid dosage forms using gamma-scintigraphy: a problem of image timing and mathematical analysis

This work was designed to identify the maximum time interval of image acquisition by gamma-scintigraphy for monitoring the emptying of a dosage form such as a tablet. Appropriate statistical parameters to describe this process were sought, including a statistical procedure for group comparisons of such data. Gamma-scintigraphy was employed in seven healthy male volunteers, who swallowed a light and a dense tablet, each 12 mm in diameter, formulated to contain different isotopes to allow identification. Images were taken sequentially at 30-s intervals to provide images of each tablet in 1-min spacing until emptying of both tablets was reported. In selecting images, it was also possible to simulate image acquisition intervals of 2, 3, 5, 10, 15, 20 and 30 min. The values derived are discrete random variables. The maximum time interval between image acquisitions that permitted reliable results to be obtained was found to be 3 min for light and 2 min for dense tablets. Consideration of the emptying of a tablet as a Bernoulli random event provided a suitable statistical approach to the analysis of such data, giving a median and an interquartile range. While the commonly applied method, which is based on parametric procedures deriving arithmetic means and standard deviations, failed to detect a difference in the emptying times of the two types of tablets, the use of non-parametric statistics (Wilcoxon test) provided a clear distinction between them in this respect. The assessment of gastric emptying by gamma-scintigraphy studies can be improved by using short image intervals and application of appropriate statistical analysis.