Feasibility study for the rapid determination of the amylose content in starch by near-infrared spectroscopy.

Near-infrared (NIR) spectroscopy was used to determine the amylose content in six different starches, whose declared amylose contents ranged from 2 to 95% m/m. The amylose content of starches can vary considerably between batches depending on growth conditions and time of harvesting. An NIR calibration model was developed for amylose using simple laboratory produced mixtures of amylose and amylopectin in different ratios. The spectral region at 1700-1800nm showed a good correlation to the amylose content of these mixtures. A simple absorbance ratio calibration model using standard normal variate and first derivative pre-treated spectra gave a root mean standard error of prediction of 1.2% m/m. Application to real samples gave amylose contents in reasonable agreement with the average values stated by the supplier. NIR spectroscopy provides a rapid and non-destructive method for the quantitative determination and standardisation of amylose in starch and could make a suitable alternative to traditional techniques, such as complex formation of starch with iodine or n-butanol.     

Theoretical and experimental investigations into the delamination tendencies of bilayer tablets

A controlled release resinate beads of betahistine diHCl (BHCl), a short half-life freely water soluble drug, was developed to allow once-daily administration to improve patient compliance and eliminate the risk of intolerance of the drug. BHCl-resin complex was subsequently coated with Eudragit RS100. A 2(4) full factorial design was employed for optimization and to explore the effect of Eudragit RS100 concentration in the coating solution (X(1)), the coating percentage (X(2)), the speed of rotation (X(3)) and the concentration of plasticizer (PEG 400) (X(4)) on the release rate of the drug from the microcapsules. The extent of coating (Y(1)), and the percentage drug released at given times (Y(2), Y(3) and Y(4)) were selected as dependent variables. The optimization process was performed for X(1), X(2), X(3) and X(4) using target ranges of these responses determined based on target release model deduced form zero-order dissolution profile of BHCl for once-daily administration. The levels of X(1), X(2), X(3) and X(4) of optimized BHCl microcapsules are 14.42%, 50.63%, 1495rpm and 9.94%, respectively. The calculated value of f(2) for the optimized BHCl microcapsules filled into hard gelatin capsules was 67.03 indicating that the dissolution profiles of the optimized formulation is comparable to that of the target release model. It could be concluded that a promising once-daily extended-release microcapsules of the highly water soluble drug, BHCl, was successfully designed.     

The influence of plate design on the properties of pellets produced by extrusion and spheronization

The aim of this work was to produce pellets using a standard formulation by means of extrusion and spheronization. Three different spheroniser friction plate patterns (i.e. cross-hatch, radial, striated edge pattern) have been used in order to investigate whether the plate pattern affects physical properties of the pellets such as pellet size distribution, yield, shape, mechanical strength, density and drug dissolution. Extrusion was performed with a screen extruder and the screen size was varied to determine whether the extrudate produced could affect the physical properties of pellets. The plate load was also varied. Diclofenac sodium was chosen as a model drug. The pattern of the friction plate used in the spheronization of extrudates affected the properties of the pellets. Yield values varied by up to 20%, and for an otherwise optimised formulation the use of a striated edge plate appeared advantageous in this respect. However, these pellets had a reduced mechanical strength despite their lower porosity, which might be disadvantageous. In addition, other factors such as the amount of extrudate loaded into the spheroniser, the maintenance of a constant moisture content within the spheroniser and the size of the extruder screen influenced these findings significantly. The only physical property of the pellets that did not respond to the various changes in the manufacturing process of the pellets is the pellet shape, which remained spherical. The dissolution of the drug appeared to be related to the median pellet size and was only marginally affected by changes in the spheronization process.     

The rheological properties of modified microcrystalline cellulose containing high levels of model drugs

The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of non-Newtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets.     

The gastric emptying of food as measured by gamma-scintigraphy and electrical impedance tomography (EIT) and its influence on the gastric emptying of tablets of different dimensions

A study in human volunteers has been designed to evaluate the influence of different food regimes on the gastric emptying of 3 mm and 10 mm diameter tablets. Dextrose and beef drinks were used as liquid food; a mixture of minced beef and mashed potato (shepherd's pie) was used as a solid meal. The gastric emptying of these foods was monitored simultaneously with electrical impedance tomography (EIT) and gamma-scintigraphy (GS), and was quantified in terms of the time before gastric emptying started, the lag time, the mean gastric residence time (MGRT) and its variance (VGRT), and the time for complete emptying. The gastric emptying time of the tablets was established by monitoring the position of the tablets, which had been labelled with suitable radio isotopes, by GS. The two systems for monitoring gastric emptying of the foods did not provide equivalent results: times obtained with EIT were generally shorter than those obtained with GS for the liquid foods, but were longer for the solid meal. There was only a slight difference in the emptying times of the two liquid foods, whereas values for MGRT, VGRT and the time for complete emptying were considerably longer for the solid meal. In nearly all instances the tablets emptied after the foods had emptied completely from the stomach. Gastric emptying times were longer for the 3 mm tablets than the 10 mm tablets, whatever food they were taken with. The difference between the median emptying times was significant when the meal was either a dextrose solution or a beef drink, but not when the meal was shepherd's pie. The increase in gastric emptying time of tablets induced by solid food was greater than that associated with the differences in tablet size. By providing a protocol that did not allow the administration of further food until after the tablets had emptied from the stomach, no tablet emptying times exceeded 6 h.     

Assessment of the in‐vivo drug release from pellets film‐coated with a dispersion of high amylose starch and ethylcellulose for potential colon delivery

Objectives The aim of this study was to test the ability of a colon targeting system comprising pellets film‐coated with a dispersion of high amylose starch (Hylon VII) and ethylcellulose (Surelease) (1 : 2 w/w) to deliver a model drug (5‐aminosalicylic acid; 5‐ASA) in vivo into the colon of rabbits. An uncoated pellet formulation was used as a control. Methods Six New Zealand female rabbits, approximately 2 kg, were randomly divided into two groups. Pellet formulations containing 50 mg/kg of 5‐ASA were filled into hard gelatin capsules size 4, and were administered orally using a cannula. The rabbits were fasted for 12 h before, and throughout, the study but had free access to water. Blood samples were collected, through a catheter inserted into the marginal vein of the ear, at pre‐determined times and the plasma analysed by a validated HPLC method with fluorescence detection. Results Analysis of the 5‐ASA plasma levels following administration of the uncoated pellets showed a C_max of 2.38 ± 0.49 μg/ml at 2 h post administration confirming that this system released the drug at an unspecific site, most likely in the rabbits' stomach and proximal small intestine. On the other hand, the coated formulation showed a delayed drug absorption (C_max 0.22 ± 0.19 μg/ml and t_max of 8 h), suggesting that the coating is able to prevent drug release in the stomach and small intestine, but allowing drug release in the colon. The coated pellets were retrieved from the rabbits' faeces after the 24‐h study. They had a drug content of < 40%, suggesting that the film‐coating had been digested by the bacterial amylases of the colon and the drug was released specifically in the colon of the rabbits. Conclusions Results from this study showed that the proposed drug delivery system has the potential to deliver drugs specifically into the colon.     

Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine

Purpose. To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract. Methods. Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-111 to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration. Results. The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and C_max parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400. Conclusions. These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.