The stability of pharmaceutical powders: effect of additives and coating

The decomposition of drugs in the solid state has been studied using aspirin and salsalate as models. The feasibility of using suspension systems for predicting the stability of these drugs in the solid state has been investigated.. It has been found that such systems are inappropriate in defining the effect of excipients on 'the decomposition of the active drug due to chqnges in the degradation pathway. Using a high performance liquid chromatographic method, magnesium stearate was shown to induce the formation of potentlally immunogenic products in aspirin powders. These products which included salicylsalicylic acid .and acetylsalicyclsalicylic acid were not detected in aspirin suspensions which had undergone the same extent of decomposition. By studying the effect of pH and of added excipients on the rate of decomposition of aspirin in suspension systems, it has been shown that excipients such as magnesium stearate containing magnesium oxide, most probably enhance the decomposition of both aspirin and salsalate by alkalinising the aqueous phase. In the solid state, pH effects produced by excipients appear to be relatively unimportant. Evidence is presented to suggest that the critical parameter is a depression in melting point induced by: the added excipient. Microscopical examination in fact showed the formation of clear liquid layers in aspirin samples containing added magnesium stearate but not in control samples. Kinetic equations which take into account both the diffusive barrier presented by the liquid films and the. geometry of the aspirin crystals were developed. Fitting of the .experimental data to these equations showed good agreement. with the postulated theory. Monitorjng of weight issues during the decomposition of aspirin revealed that in the solid systems studied where the bulk of the decomposition product sublimes, it is possible to estimate the extent of degradation from the residual weight, provided the initial weight is known. The corollary is that in such open systems, monitoring of decomposition products is inadequate for assessing the extent of decomposition. In addition to the magnesium stearate-aspirin system, mapyramine maleate-aspirin mixtures were used to model interactive systems. Work carried out in an attempt to stabilise such systems included microencapsulation and film coating. The protection obtained was dependent on the interactive species used. Gelatin for example appeared to stabilise aspirin against the adverse effects of magnesium stearate but increased its decomposition in the presence of mapyramine maleate.

Inhibition of microbial colonization of shipboard fuel systems

The aim of the investigation was to study the problem of colonization of shipboard fuel systems and to examine the effect of a number of environmental factors on microbial growth and survival in order to find potential preservative treatments. A variety of microbial species were isolated from samples taken from fuel storage tanks. Bacteria were more numerous than yeasts or fungi and most microorganisms were found at the fuel/water interface. 1he salinity, pH and phosphate concentration of some water bottoms were characteristic of sea water. Others were brackish, acidic and varied in phosphate content. Microorganisms were cultured under a number of environmental conditions. After prolonged incubation, the inoculum size had no effect on the final biomass of Cladosporium resinae but the time required to achieve the final mass decreased with increasing spore number. Undecane supported better growth of the fungus than diesel fuel and of four types of diesel fuel, two allowed more profuse growth. With sea water as the aqueous phase, a number of isolates were inhibited but the addition of nutrients allowed the development of many of the organisms. Agitation increased the growth of C. resinae on glucose but inhibited it on hydrocarbons. The optimum temperature fgr growth of C. resinae on surface culture lay between 25º C and 30º C and growth was evident at 5º C but not at 45º C. In aqueous suspension, 90% of spores were inactivated in around 60 hours at 45ºC and the same proportion of spores of C. resinae and Penicillium corylophilum were destroyed after about 30 seconds at 65ºC. The majority of bacteria and all yeasts in a water bottom sample were killed within 10 seconds at this temperature. An increase in the concentration of an organo-boron compound caused more rapid inactivation of C. resinae spores and raising the temperature from 25ºC to 45°C significantly enhanced the potency of the biocide.

The effect of certain hydrophilic polymers on suspension stability

The adsorption of nonionic surface active agents of polyoxyethylene glycol monoethers of n hexadecanols on polystyrene latex and nonionic cellulose polymers of hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose on polystyrene latex and ibuprofen drug particles have been studied. The adsorbed layer thicknesses were determined by means of microelectrophoretic and viscometric methods. The conformation of the adsorbed molecules at the solid-liquid interface was deduced from the molecular areas and the adsorbed layer thicknesses. Comparison of the adsorption results obtained from polystyrene latex and ibuprofen particles was made to explain the conformation difference between these two adsorbates. Sedimentation volumes and redispersibility values were the main criteria used to evaluate suspension stability. At low concentrations of surface active agents, hard caked suspensions were found, probably due to the attraction between the uncoated areas or, the mutual adsorption of the adsorbed molecules on the bare surface of the particles in the sediment. At high concentrations of hydroxypropyl cellulose and hydroxypropyl methylcellulose, heavily caked sediments were attributed to network structure formation by the adsorbed molecules. An attempt was made to relate the characteristics of the suspensions to the potential energy of interaction curves. Generally, the agreement between theory and experiment was good, but for hydroxyethyl cellulose-ibuprofen systems discrepancies were found. Experimental studies showed that hydroxyethyl cellulose flocculated polystyrene latex over a rather wide range of concentrations; similarly, hydroxyethyl cellulose-ibuprofen suspensions were also flocculated. Therefore, it ls suggested that a term to account for flocculation energy of the polymer should be added to the total energy of interaction. A rheometric method was employed to study the flocculation energy of the polymer.

The development, evaluation and use of freshly isolated renal proxinal tubule systems in the fischer rat

The investigation of renal pathophysiology and toxicology has traditionally been advanced by the development of increasingly defined and refined in vitro preparations. This study has sought to develop and evaluate various methods of producing pure samples of renal proximal tubules (PTs) from the Fischer rat. The introduction summarised the most common in vitro preparations together with the parameters used to monitor viability - particularly with regard to toxic events. The most prevalent isolation methods have involved the use of collagenase to produce dissociation of the cortex. However, the present study has shown that even the mildest collagenase treatment caused significant structural damage which resulted in a longevity of only 3hr in suspension. An alternative mechanical isolation technique has been developed in this study that consists of perfusion loading the renal glomeruli with Fe304 followed by disruption of the cortex by homogenisation and sequential sieving. The glomeruli are removed magnetically and the PTs then harvested by a 64μM sieve. PTs isolated in this way showed a vastly superior structural preservation over their collagenase isolated counterparts; also oxygen consumption and enzyme leakage measurements showed a longevity in excess of 6hr when incubated in a very basic medium. Attempts were then made to measure the cytosolic calcium levels in both mechanical and collagenase isolated PTs using the fluorescent calcium indicator Fura. However results were inconclusive due to significant binding of the Fura to the external PT surfaces. In conclusion, PTs prepared by the present mechanical isolation technique exhibit superior preservation and longevity compared with even the mildest collagenase isolation technique and hence appear to offer potential advantages over collagenase isolation as an in vitro renal system.

The development of a novel Bio-MEMS filtration chip for the separation of specific cells in fluid suspension

In the clinical/microbiological laboratory there are currently several ways of separating specific cells from a fluid suspension. Conventionally cells can be separated based on size, density, electrical charge, light-scattering properties, and antigenic surface properties. Separating cells using these parameters can require complex technologies and specialist equipment. This paper proposes new Bio-MEMS (microelectromechanical systems) filtration chips manufactured using deep reactive ion etching (DRIE) technology that, when used in conjunction with an optical microscope and a syringe, can filter and grade cells for size without the requirement for additional expensive equipment. These chips also offer great versatility in terms of design and their low cost allows them to be disposable, eliminating sample contamination. The pumping mechanism, unlike many other current filtration techniques, leaves samples mechanically and chemically undamaged. In this paper the principles behind harnessing passive pumping are explored, modelled, and validated against empirical data, and their integration into a microfluidic device to separate cells from a mixed population suspension is described. The design, means of manufacture, and results from preliminary tests are also presented. © IMechE 2007.