Development and application of a process window for achieving high-quality coating in a fluidized bed coating process.

Next to the coating formulation, process conditions play important roles in determining coating quality. This study aims to develop an operational window that separates layering from agglomeration regimes and, furthermore, the one that leads to the best coating quality in a fluidized bed coater. The bed relative humidity and the droplet size of the coating aerosol were predicted using a set of engineering models. The coating quality was characterized using a quantitative image analysis method, which measures the coating thickness distribution, the total porosity, and the pore size in the coating. The layering regime can be achieved by performing the coating process at a certain excess of the viscous Stokes number (DeltaSt(v)). This excess is dependent on the given bed relative humidity and droplet size. The higher the bed relative humidity, the higher is the DeltaSt(v) required to keep the process in the layering regime. Further, it is shown that using bed relative humidity and droplet size alone is not enough to obtain constant coating quality. The changes in bed relative humidity and droplet size have been identified to correlate to the fractional area of particles sprayed per unit of time. This parameter can effectively serve as an additional parameter to be considered for a better control on the coating quality. High coating quality is shown to be achieved by performing the process close to saturation and spraying droplets small enough to obtain high spraying rate, but not too small to cause incomplete coverage of the core particles.

Quantitative image analysis for evaluating the coating thickness and pore distribution in coated small particles.

PURPOSE: This study aims to develop a characterization method for coating structure based on image analysis, which is particularly promising for the rational design of coated particles in the pharmaceutical industry. METHODS: The method applies the MATLAB image processing toolbox to images of coated particles taken with Confocal Laser Scanning Microscopy (CSLM). The coating thicknesses have been determined along the particle perimeter, from which a statistical analysis could be performed to obtain relevant thickness properties, e.g. the minimum coating thickness and the span of the thickness distribution. The characterization of the pore structure involved a proper segmentation of pores from the coating and a granulometry operation. RESULTS: The presented method facilitates the quantification of porosity, thickness and pore size distribution of a coating. These parameters are considered the important coating properties, which are critical to coating functionality. Additionally, the effect of the coating process variations on coating quality can straight-forwardly be assessed. CONCLUSIONS: Enabling a good characterization of the coating qualities, the presented method can be used as a fast and effective tool to predict coating functionality. This approach also enables the influence of different process conditions on coating properties to be effectively monitored, which latterly leads to process tailoring.

Carrier diagnostics and prevention of hemoglobinopathies in early pregnancy in The Netherlands: a pilot study.

BACKGROUND: We have offered, for the first time in The Netherlands, carrier diagnostics for hemoglobinopathies (HbP) to early pregnant women. The aim of this study was to establish whether carrier analysis would be welcome by the public and feasible at the outpatient level. METHOD: One hundred and thirty-nine randomly selected women were informed and offered basic carrier diagnostics at the first pregnancy control. RESULTS: Carrier diagnostics was accepted by 136 women (97.8%). The population consisted of 31% of recent immigrants and 69% of native Dutch. One carrier of HbS and one of beta-thalassemia were found, both among the group of the recent immigrants. In both cases, partners were tested excluding a couple at risk. In addition, five carriers of alpha(+)-thalassemia were diagnosed at the molecular level, one of them in the native Dutch population. Basic carrier analysis was done both at the Hospital Laboratory and at the Reference Laboratory. No discrepancies were found. CONCLUSIONS: This pilot study shows that (1) as predicted the prevalence of risk-related HbP and of alpha(+)-thalassemia is high in the immigrant population. (2) The compliance with carrier analysis in both native Dutch and immigrants is virtually total and (3) carrier diagnosis in early pregnancy and partner analysis in Hospital Laboratories is possible and is an effective tool for primary prevention of HbP in The Netherlands.

Effects of particle size on near-wall depletion in mono-dispersed colloidal suspensions.

In this work we investigate the change in particle concentration near a solid boundary for colloidal dispersions in pressure driven flow, commonly referred to as wall depletion. In particular we determine the effect of Peclet number on the strength and spatial extent of the depleted layer. The change in concentration near the solid boundary is measured with attenuated total reflection infrared (ATR-IR) spectroscopy described previously (P.J.A. Hartman Kok et al., J. Rheol. 46 (2002) 481). The method is capable of measuring the concentration of particles at distances ranging from 0.2 to 1.0 mum from the boundary. The suspensions investigated consisted of mono-dispersed polystyrene particles in water. Particles of four different sizes were used, with radius, a, of 30, 54, 105, and 197 nm. (The ratio H/a was in the range 2500-17,000 with H being the height of the flow cell.) This enabled us to measure the wall depletion effect over a wide range of Peclet numbers, ranging from 0.01 to 45. We found that wall depletion was not significant for Peclet numbers smaller than unity. Estimates of the wall slip layer thickness obtained from rheological experiments were consistent with the results obtained by ATR-IR spectroscopy.

99mTc-PEG liposomes for the scintigraphic detection of infection and inflammation: clinical evaluation.

UNLABELLED: Polyethyleneglycol (PEG) liposomes have been shown to be excellent vehicles for scintigraphic imaging of infection and inflammation in various experimental models. In this article we report on a series of patients with possible infectious and inflammatory disease in whom the performance of 99mTc-PEG liposomes was evaluated. The results of 99mTc-PEG liposome scintigraphy were directly compared with those of 111In-immunoglobulin G (IgG) scintigraphy. METHODS: Thirty-five patients (22 men, 13 women; mean age, 51 y; range, 20-76 y), suspected of having infectious or inflammatory disease, received 740 MBq 99mTc-PEG liposomes intravenously. Imaging was performed at 4 and 24 h after injection. Patients received 75 MBq 111In-IgG 24 h after administration of the liposomes. The scintigraphic results were compared and verified by culture, biopsy, surgery, and follow-up of at least 6 mo. RESULTS: Of the 16 proven infections and inflammations, 15 were detected by 99mTc-PEG liposome scintigraphy: soft-tissue infection (n = 3), septic arthritis (n = 3), autoimmune polyarthritis (n = 2), infected hip prosthesis (n = 1), infected osteosynthesis (n = 1), spondylodiscitis (n = 1), infected aortic prosthesis (n = 1), colitis (n = 1), abdominal abscess (n = 1), and pneumonia (n = 1). 99mTc-PEG liposome and 111In-IgG scintigraphy both missed 1 case of endocarditis. In addition, an 111In-IgG scan of a patient with mild soft-tissue infection was false-negative. Concordantly false-positive scans were recorded from 2 patients, both with uninfected pseudarthrosis and focal signs of sterile inflammation. During liposomal administration, 1 patient experienced flushing and chest tightness, which rapidly disappeared after lowering the infusion rate. No other adverse events were observed. CONCLUSION: This clinical evaluation of 99mTc-PEG liposomes shows that focal infection and inflammation can be adequately imaged with this new agent. The performance of 99mTc-PEG liposomes is at least as effective as that of 111In-IgG. With the simple and safe preparation and the physical and logistic advantages of a 99mTc label, 99mTc-PEG liposomes could be an attractive agent for infection or inflammation imaging.

A particulate pulse-release system and mathematical description with the Maxwell-Stefan theory.

In this contribution both the development of a multi-particulate delayed release system with release properties dependent on the swelling of an UV crosslinked coating and a mathematical model to describe its release properties are presented. The formulation consists of a water-soluble core coated with a copolymer of methacrylic acid and ethyl acrylate. Incorporating a network of crosslinked pentaerythritol triacrylate decreases the water-solubility of the coating. After immersing the formulation in water the coating will take up water and subsequently swell in such a degree that the diffusion coefficient of water in the coating will increase. This makes the coating permeable to the dissolved components present in the core. The swelling kinetics of the coating are such that the formulation has a pulse-release profile, i.e. a fast release of the contents is obtained after a pre-determined lag-time. Both the coating thickness and the duration of the UV crosslinking time can be used to adjust the lag-time. The experimental results are used to estimate the Maxwell-Stefan diffusion coefficients of water in the coating. The relation between the Maxwell-Stefan diffusion coefficient and the mole fraction of water in the coating differs from results found in the literature. However, the prediction of the release time based on the presented model is in good agreement with the experimental findings.

HB Gouda [alpha 72(EF1)His-->Gln], a new silent alpha chain variant.

We describe a new alpha chain mutant accidentally found in a diabetic patient. The propositus is being treated for diabetes mellitus II with 4% glycated hemoglobin (Hb A1C). The variant, named Hb Gouda, is not detectable by starch gel electrophoresis but appears as a shoulder before the Hb A fraction during the chromatographic separation of Hb A1C. The hematological analysis revealed normal parameters with a normal serum iron value. No anomalies were reported in connection with Hb Gouda. The tryptic peptide map and sequencing of the alpha T-9 peptide revealed the substitution of a histidine by a glutamine at position 72. By selective amplification and sequencing of both the alpha genes, we have assigned the new mutation to the alpha 2 gene. Position 72 of the alpha chain is a moderately conserved site located between two non-conserved amino acids. This site is not involved in heme, dimer or tetramer contacts, or in Bohr effect or in 2,3-diphosphoglycerate binding.

A new procedure for the visualization of multiple forms of gamma-glutamyl transferase (GGT). Results in normals, patients receiving enzyme-inducing drugs and patients having liver parenchymal lesions.

The activity of gamma-glutamyl transferase (GGT, EC 2.3.2.2) in sera of 68 healthy individuals, of 38 patients receiving anti-epileptic drugs, and of 27 patients having liver parenchymal lesions, was visualized after electrophoresis on cellulose-acetate gel using the substrate gamma-L-glutamyl-p-nitroanilide as a new colour reagent. The liberated p-nitroaniline was converted in situ into a lilac-coloured product using the Bratton-Marshall reaction. In most samples two bands were demonstrated, one located between albumin and alpha1-globulin, called GGT 1, the other located in the alpha2-globulin region, GGT 2. In a few samples a third band, GGT 3, with far less activity than the other bands, occurred in the beta-globulin region. When it occurred, an increase in total GGT activity was mainly due to an increase of GGT-1 activity. The possible role of the determination of GGT-1 activity as a monitor of microsomal enzyme induction is discussed.

Calibration of a turbidimetric assay of serum lipase activity.

Serum lipase activity has been measured by the turbidimetric method of Shihabi and Bishop, using an olive oil suspension as substrate (Shihabi, Z.K. and Bishop, C. (1971) Clin. Chem. 17, 1150-1153). For this method we developed a new calibration procedure, which can be carried out with great precision. Moreover, the technique is simple and fast and therefore suitable for routine use in clinical chemical laboratories. The new calibration procedure consists of the continuous titration of fatty acids, liberated by lipase from the sample, under the same reaction conditions as those used in the turbidimetric assay. A close correlation has been found with the results from the method of Shihabi and Bishop, in which method calibration has been carried out by making use of the linear relationship between the olive oil concentration and the absorbance of the suspension. In our method, the numerical results are twice those obtained by the method of Shihabi and Bishop. A possible explanation for this phenomenon is given.