Effect of crystal habit on the dissolution behaviour of simvastatin crystals and its relationship to crystallization solvent properties.

Simvastatin crystals, having same crystal structure but different types of habits and hence different intrinsic dissolution rate, were prepared by recrystallization from solvents selected according to their polarity index. Scanning electron microscopy, laser diffraction, image analysis, X-ray powder diffractometry, Fourier transform infrared spectroscopy and differential scanning calorimetry were used to investigate the physicochemical characteristics of the prepared crystals. The isolated crystals exhibited different crystal habits but possessed the same internal crystal structure. In this study the comparative intrinsic dissolution behaviour of the simvastatin crystals with different types of habits was studied and explained by surface energy and correlated to different solvent systems that were used for crystallization. In our work we diminished the influence of all other physical parameters that could influence the dissolution rate, e.g. particle size, specific surface area and polymorphism in order to focus the study onto the impact of crystal shape itself on the dissolution rate of simvastatin crystals. Rod shaped crystals isolated from more hydrophilic solvent mixture dissolved faster than plate-like crystals obtained from solvent mixture with lower polarity index. We correlated this fact to the different growth rate of the individual faces which resulted in different relative size of the individual crystal faces exposed to the dissolution medium as well as the chemical nature of those faces which in turn influenced the wettability and subsequent dissolution of the active pharmaceutical ingredient.

Determination of trace elements and calcium in bone of the human iliac crest by atomic absorption spectrometry.

A rapid and reliable analytical method for the determination of trace elements in human bone by atomic absorption spectrometry is reported. Calcium was determined to estimate the homogeneity of samples. Human bone from the iliac crest was obtained at autopsy of adult subjects. Before analysis samples were decomposed by microwave digestion and acid digestion in a Parr bomb. Zinc, rubidium, strontium, calcium and iron were determined by flame atomic absorption spectrometry (FAAS) and aluminium, copper and lead by electrothermal atomic absorption spectrometry (ETAAS) at optimum measurement conditions. The results for the two digestion procedures agreed for zinc, rubidium and calcium within +/-5%, for copper within +/-7% and for strontium, iron, aluminium and lead within +/-10%. The repeatability of measurement (R.S.D.) for determination of calcium and trace elements after microwave digestion and acid digestion in a Parr bomb was tested in one representative autopsy bone sample by six parallel determinations. It was found to be better than +/-5% either for microwave digested samples or samples digested in a Parr bomb, for all elements determined by FAAS and ETAAS techniques. The accuracy of the applied digestion procedures was checked by analysis of trace elements in NIST SRM 1486 Bone Meal reference material. Good agreement of the results with certified values was obtained for both digestion procedures. The microwave procedure developed for digestion of small amounts of sample was applied in trace elements analysis of bone biopsy samples from dialysis patients.

Problems related to determination of trace elements in spent continuous ambulatory peritoneal dialysis fluids by electrothermal atomic absorption spectrometry.

Critical parameters which influence the direct determination of trace elements in spent continuous ambulatory peritoneal dialysis (CAPD) fluids by electrothermal atomic absorption spectrometry (ETAAS) were investigated. Samples were collected after CAPD fluid exchange in 5.0 ml polyethylene cups and stored at -20 degrees C. Daily spent CAPD fluids were frozen immediately, while nightly spent CAPD fluids were frozen 2-3 h after the morning exchange. Before analysis samples were equilibrated to room temperature and analysed within 8 h. It was found experimentally that some samples which were not frozen immediately leaked out of the pyrolytically coated graphite tube before the drying step. In order to keep the sample in the graphite tube and to obtain reproducible measurements of copper, aluminium and iron, samples were diluted before analysis 1 + 1 with 32% v/v nitric acid. The standard addition method was used in the calibration procedure. The results of direct ETAAS determinations for copper agreed well (+/-5-10%) with those obtained after acid digestion of CAPD fluids in Parr bomb. The procedure for direct determination of all three elements was validated with spiked samples.

Antibacterial tests of bismuth(III)-quinolone (ciprofloxacin, cf) compounds against Helicobacter pylori and some other bacteria. Crystal structure of (cfH2)2[Bi2Cl10].4H2O.

The antibacterial tests of two bismuth(III)-ciprofloxacin (cf) compounds against Helicobacter pylori (H. pylori) and some other bacteria were performed. The results have shown that the activity of both compounds is comparable to that of ciprofloxacin hydrochloride. The crystal structure of (cfH2)2[Bi2Cl10].4H2O (cfH2 = doubly protonated molecule of cf) is presented and discussed. The compound was isolated from acidic medium where quinolone is protonated and thus no bonding between quinolone and bismuth was observed. The bismuth(III) ions are coordinated by chloride ions forming dinuclear [Bi2Cl10]4- anions. The charge of this ion is compensated with protonated quinolone molecules (ionic interactions).

Preparation and characterisation of copper(II) hyaluronate.

Amorphous copper complexes of the general composition Cu(C14H20O11N)2 x xH2O have been prepared with high- and low-molecular-weight hyaluronic acid (HA). Optimal conditions for preparation are obtained at pH values from 5.0 to 5.5, with a molar ratio of HA versus Cu2+ of 1:1, and at a mass concentration of 5 and 10 mg/mL for high- (Mw = 1.8 x 10(6) Da) and low-molecular-weight sodium hyaluronate (Mw = 2 x 10(5) Da), respectively. The coordination polyhedron of the copper ion has been elucidated by EXAFS and XANES spectroscopy. Copper atoms are octahedrally coordinated in both cases with four equatorial Cu-O bond lengths of 1.95 A, and two axial Cu-O bonds of 2.46 A. Visible spectra of acidic aqueous solution suggest that substitution of axial oxygens by NH groups occurs at pH 6.5 or higher. If the pH value of the copper(II) hyaluronate solution increases above 6.5, the coordination of copper(II) changes. It is very likely that the N atom coming from the acetamido group enters into the coordination sphere of the copper(II) ion.

Optimisation of parameters for determination of rubidium in spent CAPD fluids by flame and electrothermal atomic absorption spectrometry.

An analytical procedure is reported for the determination of rubidium in spent continuous ambulatory peritoneal dialysis (CAPD) fluids by flame and electrothermal atomic absorption spectrometry (FAAS, ETAAS). Samples of spent CAPD fluids were collected as 5 ml aliquots in polyethylene tubes and stored in a freezer at -20 degrees C. Before analysis, samples were equilibrated to room temperature and analysed within 8 h. A total of 2 mg ml(-1) of caesium was added to each sample and standard solution to overcome interferences from ionisation. An air-acetylene flame was applied in FAAS determinations. Analysis was performed against aqueous standards. The calibration graph was linear from 30.0 up to 5000 microg l(-1) Rb, while the limit of detection (3 s) was found to be 20.0 microg l(-1) rubidium. Good repeatability of measurement (RSD 1%) was obtained. Parameters were also optimised for determination of rubidium in spent CAPD fluids by ETAAS. Ten-fold diluted samples (3.5% nitric acid) were analysed applying standard addition calibration. The calibration graph was linear from 2.0 up to 30.0 microg l(-1) rubidium, while the limit of detection (3 s) was found to be 1.0 microg l(-1) rubidium (sample volume 10 microl). Good repeatability of measurement (RSD 5%) was obtained. The results of direct determination by FAAS and ETAAS were compared to those obtained after acid digestion of samples in Parr bombs. The accuracy of the procedure for direct determination was checked by spiking samples. In 73% of samples analysed, the differences between the results obtained by the two techniques, either for direct determinations of samples or for samples digested in a Parr bomb did not exceed +/-10%.

Use of nitric acid in sample pretreatment for determination of trace elements in various biological samples by ETAAS.

Trace elements in liquid biological samples may be determined by direct electrothermal atomic absorption spectrometry (ETAAS). In our previous work it was found that samples containing proteins or DNA may leak out of the graphite tube before the drying step, despite the addition of various modifiers. In order to keep the sample to the graphite tube, samples were diluted before analysis 1 + 1 with 32% v/v nitric acid, or 5 microl of 32% v/v nitric acid was added to the graphite tube before ETAAS determination. Applying the proposed procedure, the concentrations of lead in eluted fractions after gel chromatographic separation of human cerebellar nucleus dentatus supernatant and platinum in isolated DNA samples were determined. The use of nitric acid in sample pretreatment prevent sample leakage out of the graphite tube, provided for even drying and considerably reduced nonspecific absorption in lead determination. The repeatability of measurements was better than + 6%. The accuracy of the procedure was checked by spiking samples. The recoveries for both elements lay between 93--104%. Nitric acid was found to be a better modifier than TRITON X-100.

Optimization of melt pelletization in a high shear mixer.

The effects of process conditions and binder content on the process yield and pellet characteristics of two formulations prepared by melt pelletization in a laboratory-type high shear mixer were investigated. The formulations were prepared using Gelucire 50/13 and Lutrol F68 as meltable binders. The factors under investigation were impeller speed, mixing time, mixer load, binder concentration, and their reciprocal interactions. Analysis of variance (ANOVA) was used in order to study the significance of above mentioned process variables on the useful yield. Twenty-seven experiments were required for the response surface methodology based on Box-Behnken experimental design (24 combinations with three replications of the centre point) for each formulation. The control over the process and the quality of the resulting pellets were found to depend on the rheological properties of the binders used. In the case of a low viscosity binder (Gelucire 50/13), the process was easily controllable whereas in the case of a high viscosity binder (Lutrol F68), the process was more difficult to control. The useful yield of the formulation in the case of the low viscosity binder was found to be mostly influenced by the concentration of the binder. On the other hand, different binder concentrations did not affect the useful yield of the formulation prepared by use of the high viscosity binder. In the latter case, mixing time was identified as the variable that mostly influenced the pelletization process. Finally response surface methodology was applied to find the optimum values of the process variables.

The influence of magnesium stearate on the characteristics of mucoadhesive microspheres.

Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, x-ray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential scanning calorimetry. No differences were observed in the physical state of pipemidic acid and in microsphere shape and surface between different size fractions of microspheres, prepared with different amounts of magnesium stearate. Additionally, no correlation between the physical state of the drug in different microspheres and their biopharmaceutical properties was found.

Environmentally safe sewage sludge disposal: the impact of liming on the behaviour of Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn.

Dewatered sewage sludge containing relatively high total concentrations of Cr (945 micrograms ml-1), Cu (523 micrograms ml-1), Ni (1186 micrograms ml-1) and Zn (2950 micrograms ml-1) was treated with quicklime and sawdust for sludge disinfection and post-stabilisation. The mobility of the heavy metals in the sludge samples was assessed by applying a modified five-step Tessier sequential extraction procedure. Water was added as a first step for estimation of the proportion of the easily soluble metal fractions. To check the precision of the analytical work the concentrations of heavy metals in steps 1-6 of the extraction procedure were summed and compared to the total metal concentrations. The mass balance agreed within +/- 3% for Cd, Cu, Cr, and Zn and within +/- 5% for Ni, Pb, Fe and Mn. Data from the partitioning study indicate that in the lime-treated sludge at a pH of 12 the mobility of Cu and Ni notably increased with the solubilisation of these metals from their organic and/or carbonate and Fe and Mn oxide and hydroxide fractions, respectively. Liming slightly decreased the proportion of other heavy metals in the easily soluble fractions while its impact on the partitioning between other sludge phases was almost insignificant. Due to the increased solubility of Ni and Cu as well as potential Cr oxidation at high pH, liming cannot be recommended for sludge disinfection. Addition of sawdust did not change the heavy metal partitioning.