Importance of the fraction of microcrystalline cellulose and spheronization speed on the properties of extruded pellets made from binary mixtures.

The aim of the study was to prove the importance of the binary mixture composition and spheronization speed on pellet properties. Extrudates from different binary mixtures of microcrystalline cellulose (MCC) and dicalcium phosphate dihydrate were prepared with a power-consumption-controlled extruder and spheronized at different speeds. The water content of the extrudate for the production of spherical pellets was evaluated. The pellets were characterized in terms of size, shape, porosity, mechanical properties, and disintegration. The fraction of MCC in the binary mixtures had the highest impact on the pellet properties. With an increasing fraction of MCC more water was required for successful pelletization, size and porosity of the pellets decreased, and the surface tensile stress increased. These observations were evaluated using the "sponge" and the "crystallite--gel" models for MCC. The latter led to the conception that an extrudate consists of two phases: a percolating crystallite--gel phase formed by MCC and water during extrusion and a filler phase formed by the second component of the binary mixture. This two-phase concept provides explanations for the extent of shrinking during drying and for the disintegration behavior. The spheronization speed had an influence on the size but not on porosity or surface tensile stress of the pellets. The best results were obtained at intermediate spheronization velocities of 10 and 13.4 m/sec. Fundamental properties of extrudates and pellets can be described by applying a two-phase concept of the crystallite--gel model.

Influence of neutron activation factors on the physico-chemical properties of suppositories and their excipients.

The effect of the neutron activation factors, i.e., admixture of samarium oxide (Sm2O3) and irradiation time, on the physico-chemical properties of the raw materials and the in vitro dissolution and disintegration of hydrophilic and lipophilic suppositories was investigated. It was possible to expose the pure bases and the model drugs (5-aminosalicylic acid [5-ASA] and ropivacaine hydrochloride) to 1 min of neutron irradiation in a flux of 1.1.1013 n cm-2s-1. The dissolution and disintegration of the corresponding suppositories showed that the physico-chemical properties and the fraction of incorporated drug together with the lipophilic/hydrophilic nature of the base were important factors. Sm2O3 increased the disintegration time of hydrophilic suppositories containing 5-ASA, while the dissolution of both drugs from these formulations remained unchanged. Sm2O3 did not alter the disintegration time of the lipophilic formulations, but it reduced the dissolution of both drugs from these suppositories. Irradiation induced different behaviour in the different bases.

Effects of thermal neutron irradiation on some potential excipients for colonic delivery systems.

Different excipients, which are currently being studied for colon delivery systems, were examined with respect to their stability toward neutron irradiation as a potential method of radiolabeling the formulations for gamma-scintigraphic studies. Three different pectin and four different hydroxypropyl methylcellulose (HPMC) types, in addition to two types of polymethacrylate films, were exposed to 1, 2, and 3 min of thermal neutron irradiation in a flux of 1.1 x 10(13) n cm-2 s-1. The physicochemical characteristics of pectins and HPMCs and the mechanical properties of the polymethacrylate films were examined after the radioactivity of the samples had declined to background levels. Methods included ultraviolet (UV) and Fourier transform infrared (FTIR) spectroscopy, pH measurements, loss on drying, thermogravimetric analysis (TGA), viscosimetry, gas chromatographic (GC) analysis of pectin monosaccharides, and tensile strength testing of the films. The results suggest that pectins and HPMCs undergo degradation, as expressed by a significant reduction in the dynamic and intrinsic viscosities of the samples. Generally, HPMCs were more sensitive than pectins to neutron irradiation. However, calcium pectinate proved to be the most sensitive among all the investigated polymers. Both polymethacrylate films (Eudragit L and S) resisted loss of mechanical properties following 1 and 2 min of neutron irradiation, whereas irradiation for 3 min implied significant changes in the appearance and the mechanical properties of Eudragit L films. As a conclusion, neutron irradiation results in dose-dependent degradation of the investigated polysaccharides and polymethacrylates. The consequences on the in vitro behavior of a formulation containing such polymers are discussed.

Influence of neutron irradiation on Eudragit coated tablets: validation of neutron activation II.

The in vitro characteristics of enteric coated acetylsalicylic acid tablets and cores were compared before and after irradiation with thermal neutrons, 2, 4, 7 or 15 min at 1.1.1013 neutrons cm-2s-I. The irradiation procedure affected the coated formulation to a greater extent than the cores. Drug release from tablets was already affected after 2 min of exposure, whereas the cores showed no significant inhibition of release until after 15 min of irradiation, leading to the conclusion that the effects of irradiation were caused by a combination of changes both in the core and the coating. Both tablets and cores showed an increase in the disintegration time following irradiation. Scanning electron micrographs (SEM) of non-irradiated cores/tablets and cores/tablets irradiated for 15 min, showed clear differences in the structure of the surface. SEM of the tablets irradiated for 15 min, showed that the irradiation had caused the film to loosen from the core in several places. SEM of the cross-sections of both irradiated tablets and cores showed a partially melted surface above stacked layers with reduced porosity.

Influence of the coating thickness and type of oral delivery system (tablets, pellets) on the stability towards degradation by neutron irradiation. Validation of neutron activation III.

Enteric coated dexchlorpheniramine maleate (DCPA) tablets and pellets with varying coating thickness were subjected to several in vitro tests after irradiation by thermal neutrons in a flux of 1. 1 x 10(13) n cm-2 s-1 for 2, 4 or 15 min. The appearance of the tablet formulation changed extensively after exposure of the tablets to pile radiation. The irradiation caused the film to loosen from the surface of the core, indicating the generation of gases during the irradiation process. Already after irradiating the tablets for 2 min the disintegration and dissolution behaviour were significantly changed. The extent of tablet damage increased with increasing time of exposure and increasing thickness of the coating. Compared with the tablet formulation, the cores could resist a larger amount of irradiation since dissolution behaviour of the cores was only affected after 15 min of irradiation. This indicates that the irradiation procedure initially affects the coating of the formulation. Although the dissolution behaviour of the pellet formulations changed significantly after the irradiation procedure, the changes were too small to be attributed exclusively to radiation damage.

Characterization of enteric-coated tablets and pellets by two in vitro dissolution methods and by scanning electron microscopy.

The in vitro dissolution rates of enteric-coated pellets and tablets containing dexchlorpheniramine maleate (DCPM) were obtained using the USP XXI paddle and a flow-through method. Pellets were produced by extrusion and spheronization. Tablets were produced by direct compaction, and by wet granulation. The products were coated with different amounts of Eudragit L30D using fluid-bed technology. Onset of release, determined by fitting of the Weibull function, was the only factor found to be affected by the amount of coating of the tablets. For pellets, both onset of release and dissolution rate showed significant differences. Scanning electron microscopy was used to study the effect of different dissolution media on the coating. Acidic medium was found to alter the coating surface, but the coating did not rupture during the time used in this study.

The mechanism of particulate contamination in soft polyvinyl chloride infusion fluid bags.

In the seventies, it was shown that particles were generated in soft polyvinyl chloride (PVC) infusion fluid bags when they were shaken. In this investigation an exponentially modified log-normal distribution (EMLN) is fitted to the particle data. Using the formula for the volume of a sphere, the number-density distribution is converted into a volume-density distribution. The total particle load in the samples is estimated by integration for total particle volume. The results are expressed as volume concentration in plain SI-units (microliters/l). A four-factor analysis of variance demonstrates that the mechanism of the contamination process is most probably an emulsification of low molecular weight additives in the PVC plastic, i.e. di(2-ethylhexyl) phthalate (DEHP), epoxidized vegetable oils (EVO), and others.

The covariation of chemical contamination, particulate matter and turbidity in soft polyvinyl chloride infusion fluid bags.

About 200 samples of normal saline, isotonic glucose and Ringer acetate infusions in soft polyvinyl chloride (PVC) bags obtained from three manufacturers have been analyzed by conductometric particle counting, turbidimetry and gas liquid chromatography (GLC). The particle counts were fitted to an exponentially modified log-normal model and integrated for total particle-volume. Di(2-ethylhexyl) phthalate (DEHP) and epoxidized vegetable oils (EVO), which are the main water insoluble contaminants in PVC fluid bags, were determined by GLC. There was a strong linear correlation between turbidity and GLC results. The correlation between particle-volume concentration and the DEHP and EVO concentrations was fairly good. The results seem to verify that an emulsion of plastic additives is formed when soft PVC infusion fluid bags are shaken.

Determination by gas-liquid chromatography of trace amounts of soft polyvinyl chloride plastic additives in aqueous solutions. I. Epoxidized vegetable oils.

A gas-liquid chromatographic method for the determination of epoxidized vegetable oils (EVO), such as epoxidized soybean oil and epoxidized linseed oil, in aqueous solutions is described. The EVOs are extracted with n-hexane and transesterified to the methyl esters by sodium methoxide in methanol. 3% OV-210 is used as the stationary phase. The weakest standard solution corresponds to 5 micrograms/l (5 ppb) of EVO in an aqueous sample. The reproducibility of a single analysis is 5%. The method is used for the determination of EVO in intravenous fluids stored in flexible polyvinyl chloride bags.

Determination by gas-liquid chromatography of trace amounts of soft polyvinyl chloride plastic additives in aqueous solutions. II. Di(2-ethylhexyl) phthalate, epoxidized vegetable oils and stearates.

A method for the determination of di(2-ethylhexyl) phthalate (DEHP), epoxidized vegetable oils (EVO) and stearates in aqueous solutions is described. A stepwise extraction procedure is employed to separate DEHP and EVO from the stearates, using n-hexane as extraction solvent. EVO is transesterified to methyl esters by sodium methoxide in methanol. The stearates are derivatized by methanol containing sulfuric acid. The alkyl esters are analyzed by gas-liquid chromatography, using 3% OV-210 as the stationary phase. The concentrations of the weakest standard solutions correspond to 10, 5 and 8 micrograms/l (ppb) of DEHP, EVO and stearates, respectively, in the aqueous samples. The method is used for the determination of DEHP, EVO and stearates in intravenous solutions stored in flexible polyvinyl chloride bags.

The influence of product factors on the migration in soft polyvinyl chloride infusion fluid bags.

The concentration of epoxidized vegetable oils (EVO) and di(2-ethylhexyl) phthalate (DEHP) in infusion fluids in soft polyvinyl chloride (PVC) bags has been determined by gas-liquid chromatography prior to and after agitation. Normal saline, isotonic glucose and Ringer acetate from four different manufacturers were investigated. Agitation resulted in an increased concentration of EVO and DEHP. Significant differences in contamination level were observed between solutions of different compositions and in synonymous preparations from different manufacturers. The results indicated that the total amount of migrating EVO and DEHP was affected by the pH of the solution and by the age of the plastic material. It is suggested that the migration of EVO and DEHP during agitation is influenced by the concentration of plastic degradation products.

The influence of mono(2-ethylhexyl) phthalate and stearates on the migration in soft polyvinyl chloride infusion fluid bags.

The influence of mono(2-ethylhexyl) phthalate (MEHP) and stearates on the migration of di(2-ethylhexyl) phthalate (DEHP) and epoxidized vegetable oils (EVO) in soft polyvinyl chloride infusion fluid bags during agitation has been investigated by gas-liquid chromatography. Normal saline, isotonic glucose and Ringer acetate from 3 different manufacturers were investigated. A covariation was observed between the MEHP concentration in the solution and the pH. The MEHP concentration was not influenced by agitation. There was no correlation between the MEHP concentration in the solution and the migration of EVO and DEHP, or between the stearate concentration and the EVO and DEHP migration.

Migration of plastic additives from soft polyvinyl chloride bags into normal saline and glucose infusions.

Samples of soft polyvinyl chloride (PVC) fluid bags containing normal saline and glucose 50 mg/ml were analyzed for plastic additives. The bags were shaken for 24 hours before analysis. The PVC plastic materials contained di(2-ethylhexyl)phthalate, epoxidized vegetable oils and stearates as the main additives. The same components were found in the solutions. Mono(2-ethylhexyl)phthalate was detected only in the solutions.

Maintenance therapy with a new retard tablet preparation of procainamide.

The procainamide plasma concentration was followed during maintenance therapy with a new procainamide retard tablet preparation in 23 hospitalized patients suffering from acute or chronic coronary heart disease with complicating ventricular arrhythmias. After initial individually adjusted treatment with Pronestyl every third hour, either orally or intramuscularly, for at least eight dose intervals, the retard tablets were given at 6 hour intervals for 2 to 12 days, or more. In 19 patients with no major fluctuations in their circulatory or renal state, adequate and relatively stable plasma procainamide concentration was obtained upon a constant dose of the retard preparation. On an average, the difference from minimum to maximum concentration was 55 per cent within the 6 hour dose intervals. In four patients with unstable circulation and/or renal function, procainamide therapy had to be disrupted in two because of severe side effects and toxic concentrations, and the dose was adjusted in the remaining two. It is concluded that the formulation of procainamide tablet preparations has simplified procainamide therapy within and outside hospital and improved our possibilities to perform short-and long-term studies on the risk/ benefit ratio of procainamide treatment in patients with severe ventricular arrhythmias.