Robustness of a continuous direct compression line against disturbances in feeding.

The aim of the current study was to characterize the robustness of an integrated continuous direct compression (CDC) line against disturbances from feeding, i.e. impulses of API and short step disturbances. These disturbances mimicked typical variations that can be encountered during long-term manufacture. The study included a primary formulation, with API of standard particle size, which was manufactured at 5 and 10 kg/h production rates, and a modified formulation, with API of large particle size, which was manufactured at 5 kg/h production rate. Overall, the CDC line smoothened all the disturbances, fulfilling the USP uniformity of dosage units (UDU) limit for single tablets. However, runs with the modified formulation failed the pharmacopoeia UDU requirements for the entire run due to high variation between tablets. The primary formulation passed the requirements in all cases. The residence time distribution (RTD) results indicated that the primary formulation allowed better smoothening ability, and an increase in production rate led to poorer smoothening due to shorter RTD. The RTDs revealed that a substantial part of back-mixing took place after the blender. Thus, the tablet press has an important role in smoothening disturbances longer than the mean residence time of the blender, which was very short.

The influence of complexing agents on the solubility and absorption of aluminium in rats exposed to aluminium in water.

The influence of citrate (0-31 mM), fluoride (0 or 2.6 mM) and silicate (0 or 2.6 mM) on the absorption of Al (0-18 mM) was studied in rats. We tested the hypothesis that the solubility and absorption of Al increases in the gastrointestinal (GI) tract in the presence of the complexing agents. Male rats were exposed for 6 or 7 weeks to soluble Al in acidic drinking water (pH 2.5-3.0) with or without the complexing agents. At the end of exposure Al was fractionated in the stomach content, in order to study if the solubility of Al was changed after ingestion. Al absorption was estimated by Al analysis of the right femur bone. Speciation calculations indicated that citrate and fluoride caused formation of soluble Al-citrate (97%) and -fluoride (> 60%) complexes in the water. Silicate did not affect the theoretical speciation. In all cases, a large fraction of soluble Al became insoluble in the stomach after ingestion. The concentration of soluble Al increased only in the presence of citrate or a mixture of fluoride and silicate, but citrate was the only complexing agent that influenced the absorption of Al in the rat. This indicates that the form of Al may be changed in the GI tract when soluble drinking-water Al is ingested, and that the solubility of Al in drinking water and GI tract may not be good predictors of the bioavailability of Al even when chelating agents are present.

On-line process control of liquid chromatography.

Many analytical methods are based on liquid chromatography and typically the only measure of system stability is standards, injected repeatedly throughout the sequence. In this paper, a novel approach is presented, where the analytical run is treated as a process with the chromatographic data as the product. It is postulated that enhanced quality of the data can be obtained through monitoring the process, i.e., the chromatographic system, during the sequence. For this purpose, a liquid chromatography process control (LCPC) system has been developed. Here, several parameters, e.g., the pressure at the column and the injection valve, are monitored. Chemometrics is used for interpreting the data and producing multivariate statistical process control (MSPC) charts. The chromatographic run is divided into two parts: the dynamic injection phase and the static elution phase. Two principal component analysis (PCA) models, one for each phase, are continuously created and upgraded as the data are collected. The results of the PCA are shown in the MSPC charts, and when an error detection limit is exceeded, the analyst is promptly notified. LCPC, a continuous system suitability test, provides better control of the analysis, allowing a reduction in the number of standards and replicates. Furthermore, troubleshooting is facilitated.

Does aluminium stimulate the immune system in male rats after oral exposure?

The influence of oral aluminium exposure on the immune system was studied in rats. Male rats were exposed to soluble and labile Al in acidic drinking water (0-500 mg Al/l) for 7-9 weeks. The concentration of Al in femur bone was higher in rats exposed to 50 and 500 mg Al/l (mean concentration 277 and 599 ng Al/g) than in control rats (150 ng Al/g). The Al concentration in blood plasma could only be quantified in the 500 mg/l group (mean 2.7 ng/ml), whereas the concentrations in the control and 50 mg/l groups were low (< 2 ng Al/ml). Exposure of 4-13-weeks-old rats to the highest Al concentration caused an increased number of splenocytes, whereas exposure of 9-16-weeks-old rats to 500 mg Al/l caused an increased number of thymocytes. Moreover, the proliferative response of splenocytes to the mitogen Con A (2 micrograms/ml) was increased by exposure of the 9-16-weeks-old rats to 500 mg Al/l as compared with the controls. The results indicate that oral Al exposure caused a slight stimulation of some immune functions in the rat at Al plasma concentrations normally found in the human population (< 10 ng Al/ml).

Concentration-dependent absorption of aluminum in rats exposed to labile aluminum in drinking water.

The hypothesis was tested that the absorption of labile Al in rats will increase when the Al-binding capacity of food components in the stomach is saturated. Male rats were exposed to 0, 10, 50, or 500 mg labile Al/L in acidic drinking water (pH 3) for 9 wk. The results show that labile Al in drinking water is complexed by feed constituents in the stomach of the rat in vivo, thus causing a nondetectable absorption of Al at 10 mg Al/L. An increased absorption of Al at 50 and 500 mg Al/L was associated with a saturation of the Al-binding capacity of feed components in the lumen of the stomach, causing the appearance of labile Al. Thus, the presence of labile Al in drinking water does not necessarily result in a high Al absorption when the water is ingested, since the bioavailability of labile Al is dependent both on the amount and composition of Al-binding components present in the gastrointestinal tract at the time of ingestion of the water. It is thus not possible to predict the body burden of Al in humans just by measuring the Al concentrations in drinking water. Even a further refining of the exposure measurement to include speciation of Al in the water may not markedly improve the prediction of the Al body burden. Future epidemiological studies must therefore be based on actual measurements of Al concentration in tissues or fluids from the study subjects.

Bioavailability of labile aluminium in acidic drinking water: a study in the rat.

The bioavailability of labile Al (Allab; Al3+, and monomeric hydroxo and sulfato complexes) in drinking water was studied in the rat. The hypothesis was that Allab in drinking water is more available for absorption in the gastro-intestinal tract than Al complexed in the rat feed. Male Sprague-Dawley rats were exposed to 4 mg Al/litre in acidic drinking water (pH 4-5) and 5 mg Al/kg in the feed for 10 wk. The Al intake of these rats was about twice that in a control group of rats that received Al only in the feed. Both a theoretical speciation calculation and a speciation analysis of the water in a flow injection system showed that more than 98% of the Al in the water was present as Allab. However, intake of this water did not result in increased levels of Al in the bone, liver or brain tissue of the rats. Al speciation in a simulated rat stomach indicated that Allab in drinking water is rapidly complexed by feed constituents as the water enters the acidic milieu of the stomach, resulting in a very low concentration of Allab. The concentration of dissolved Al was also low in comparison to the added amount of labile Al. The possibility of complex formation between Allab and feed components in the gastro-intestinal tract should be taken into account in further studies of the bioavailability of drinking water Al in experimental animals and in humans.

Aluminium fractionation in a simulated rat stomach: an in vitro study.

This study is part of a project dealing with the absorption of aluminium in rats from acidified drinking water. The hypothesis of the project was that 'labile' forms of aluminium in water might be more available for absorption than aluminium in food. To investigate this hypothesis, the distribution of species of the metal within the rat stomach must be considered. So far, few attempts in this direction have been made. The distribution of aluminium forms in vitro was studied, simulating the conditions present in a rat stomach. The in vitro set-up is based on methods used for drug release studies. The results show that only part of the aluminium (29-54%) added in 'labile' forms at a concentration of 4.0 mg l-1 Al was detected as total dissolved aluminium (Altot) after incubation in a simulated rat stomach. The levels of 'quickly reacting aluminium' (Alqr) (approximately the sum of Al and its monomeric hydroxo and sulfato complexes) were very low (< 0.2 mg l-1), but difficult to quantify precisely in this matrix. The pattern of the in vitro results was confirmed by measurements in pooled rat stomachs from in vivo experiments. There are obviously considerable amounts of ligands present in rat feed that bind strongly to aluminium and thereby affect the distribution of metal species inside the rat stomach. It is believed that phosphoserine, present in the protein casein, is an important ligand for aluminium complexation in this case. The results show that studies of Al absorption should be accompanied by fractionation measurements within simulated or real gastric systems.