Extrusion/spheronization--effect of moisture content and spheronization time on pellet characteristics.

As part of a larger effort aimed at optimizing the properties of pellets produced by spheronization of extruded masses, the effect of the moisture content of wet masses on extrusion force and torque was studied. The wet masses were composed of either microcrystalline cellulose (MCC) or mixtures of MCC with lactose or dicalcium phosphate. Based on the force and torque data, a moisture content "window" was defined for consistent extrusion. Moisture exerts a lubricant effect, and a moisture level of 100-120% w/w dry solid seemed necessary for the extrusion of MCC into rod-shaped, discrete pieces. Screen force clearly depended on the moisture content but was relatively insensitive to extruder speed, especially at 80% and 100% moisture content. The physical properties of pellets as a function of spheronization time were studied by sampling the material at known intervals. The percent yield, tapped density, and a two-dimensional sphericity index of an 18/20 mesh fraction of pellets were measured. Maximum yield, tapped density, and sphericity were achieved within 60 sec in the spheronizer. With increasing residence time, the shape and density were unchanged while the yield was severely reduced. Among the formulations studied, pellets with equal amounts of lactose and MCC were superior to those of pure MCC in yield, density, and sphericity. Based on these results, an outline to optimize the endpoint of the spheronization process for formulations containing MCC is suggested.

Physico-mechanical characterization of the extrusion-spheronization process. Part II: Rheological determinants for successful extrusion and spheronization.

Spheres are widely used as the basis for the design of multiparticulate drug delivery systems. Although the extrusion and spheronization processes are frequently used to produce such spheres, there is a lack of basic understanding of these processes and of the requisite properties of excipients and formulations. It is hypothesized that the rheological or mechanical properties of the wet mass may address the requirements of both extrusion and spheronization. The fact that certain formulations can be extruded, yet not be successfully spheronized, suggests that the two processes depend on different formulation attributes, and that there are different rheological criteria that must be met for each process to be successful. As a preliminary test of these hypotheses, methods were developed to measure the rheological behavior and mechanical properties (plastic yield value, tensile strength, yield loci) of the wet mass and/or extrudate for a model formulation system (microcrystalline cellulose, lactose, hydroxypropylmethylcellulose). The finished spheres were characterized in terms of particle size, bulk density, individual bead crushing strength, and sphericity. A Box-Behnken experimental design was employed by which the independent formulation variables could be related to the dependent rheological/mechanical properties and finished pellet characteristics. It was observed that there was a critical range of rheological/mechanical variables within which pellets having desirable criteria such as yield of 18/25 mesh cut > 60%, a shape factor > 0.85, etc., can be prepared. Screen pressure was shown to be the most critical variable affecting the yield of 18/25 mesh cut, while the yield value and tensile strength markedly influenced the shape factor. Thus, for the formulations studied, it was possible to define a "window" of rheological/mechanical properties within which both extrusion and spheronization can be successfully carried out.

Physicomechanical characterization of the extrusion-spheronization process. I. Instrumentation of the extruder.

Extrusion-spheronization is a popular means of producing spheres which can be coated to form a controlled-release system. In the extrusion process, stress is necessary to force a wet mass through small orifices, and as a result, frictional heat builds up at the screen. Therefore, the quantitative measurement of the screen pressure and screen temperature is described and shown to provide objective measures of extrudability. A strain gauge load cell was mounted tangentially to the screen of a Luwa EXDS-60 extruder with a specifically fabricated holder. The load cell output was calibrated in terms of pressure inside the screen with a special rubber plug system. A fast-response thermocouple was used to measure the screen temperature. Experiments with 50/50 lactose/Avicel PH101 revealed that a linear relationship exists between the amount of water used in the granulation and the screen pressure, that the percentage open area of the screen determines the rank order of the screen pressure, and that the maximal yield of 18/25-mesh cut pellets was uniquely related to the screen pressure. Also, a high degree of correlation was observed between the screen pressure and the screen temperature.

Evidence for Two Indoleacetic Acid-Induced Growth Responses in the Avena Straight-Growth Indoleacetic Acid Assay.

Floating Avena sativa L. cv Victory coleoptile segments were used to determine whether the straight-growth indoleacetic acid (IAA) assay can be reconciled with the Avena curvature assay and the Cholodny-Went theory of photo- and gravitropism. Measurements of segment length after 5 h yield sigmoid-shaped IAA dose-response curves with the growth rate leveling off at 1 [mu]M. However, measurements made at 24 h generate bell-shaped curves with maximal growth being induced by 10 [mu]M IAA. The difference between short- and long-term IAA dose-response curves is not due to IAA degradation; instead, it is the result of two growth responses to IAA. The initial one is rapid, responds to low concentrations of IAA, and lasts for 12 h. The second response is less sensitive to IAA than the first one. It appears after 6 h but is not obvious until the last 12 h of a 24-h incubation. The profile of short-term IAA dose-response curves reflects the initial growth response, whereas that of the 24-h curve is the sum of both growth responses. Linear-linear plots of 5- and 24-h dose-response curves show that coleoptile segment growth rate is proportional to IAA concentration up to 0.3 [mu]M. When the efficiency of IAA action is taken into account, it is found that the most effective IAA concentration for short and long incubations is 0.4 [mu]M. It is concluded that the Avena straight-growth IAA assay is as sensitive as the Avena coleoptile curvature assay, and that it is consistent with the Cholodny-Went theory.

Methods for the assessment of the stability of tablet disintegrants.

To allow assessment of the long-term stability of tablet disintegrants, two mechanisms for their functionality (i.e., water uptake and swelling force generation) were monitored. Three disintegrants, alginic acid, sodium starch glycolate, and crospovidone, were used to establish the methodology. The water uptake and swelling force methodologies developed were reproducible, thus allowing for the evaluation of the effect of time, temperature, and humidity on these properties of disintegrants. The data obtained suggest that the process of water uptake and swelling force generation was essentially a two-step process. Initially, water entered the pore space in the powder bed; there was a definitive lag time before a swelling force was generated. In the stability evaluation of alginic acid and sodium starch glycolate, samples were stored for 1-year. Above 30 degrees C and 75% relative humidity, the swelling force performance of alginic acid was markedly affected. Changes seen with sodium starch glycolate were much less marked.

Pharmacokinetics of ivermectin administered intravenously to cattle.

Ivermectin, a macrocyclic lactone disaccharide antiparasitic agent, was administered intravenously to six young calves (one bull, five steers) as a bolus dose of 200 micrograms/kg. The disposition kinetics of ivermectin in cattle can be described by a three-compartment open model with elimination from the central compartment. Compartmental analysis yielded mean parameters as follows: terminal elimination rate constant (beta) = 0.258 d-1, biological half-life (t 1/2 beta) = 2.7 d; apparent volume of distribution of the central compartment (Vd1) = 0.45 L/kg; apparent volume of distribution at steady state (Vdss) = 2.4 L/kg. The area under the plasma concentration-time curve (AUC) was 254 ng X d/mL. Noncompartmental parameters, obtained by utilizing statistical moment theory, mean residence time (MRT), clearance (CL), and Vdss were calculated to be 2.8 d, 0.79 L/kg X d, and 2.2 L/kg, respectively.

Oral controlled-release delivery of ivermectin in cattle via an osmotic pump.

Ivermectin, a potent antiparasitic agent with activity against internal and external parasites, was delivered to cattle at a controlled zero-order rate for 35 d via orally administered, specially weighted, ALZET 2ML4 osmotic pumps. The osmotic pumps delivered the drug consistently over the trial period. Steady-state levels in plasma were achieved in 7-14 d, and plasma concentration depletion curves were observed to start at approximately day 35, the theoretical delivery lifetime of the osmotic pumps. Bioavailability was estimated to be 40%, and dose rate-plasma steady-state interrelationships were shown to be linear.

The effect of cytochalasin B on the rate of growth and ultrastructure of wheat coleoptiles and maize roots.

Cytochalasin B (CB) inhibits the elongation growth of maize roots, and that of wheat coleoptile segments incubated in indolyl-3-acetic acid, by over 30% after a lag period of about 60 min. This long lag is not due to poor tissue penetration by the inhibitor, but seems to reflect a property of the process inhibited by CB. The only visible ultrastructural change accompanying growth inhibition is the accumulation of secretory vesicles in the vicinity of dictyosomes, which occurs between 90 and 300 min. However, a massive accumulation of vesicles is seen after 120 min in root cap cells which possess very active dictyosomes. The results indicate that CB does not inhibit elongation growth by interfering with cytoplasmic streaming. Instead, they indicate that the drug acts to inhibit the secretion of cell wall components at some stage after vesicle production, but prior to their transport.

Does indoleacetic acid promote growth via cell wall acidification?

Growth of Triticum aestivum L. cv. Cappelle Desprez coleoptiles is promoted by 5.7×10(-5) M indole acetic acid (IAA) as effectively in pH 3.4 buffer as in water, but IAA is not effective in the presence of buffer at pH 3.0 or 3.2 A combination of 5.7×10(-5) M IAA and pH 3.4 buffer promotes growth to a greater extent than pH 3.2 buffer alone, which is optimal for acid-induced growth. IAA employed at 10(-7) M is still effective at promoting growth in the presence of pH 3.4 buffer, moreover, IAA at 10(-7) M interacts synergistically with the acidic buffer to promote growth. It is concluded that IAA and acid promote growth via separate mechanisms, and that IAA does not promote cell wall loosening by rendering the cell wall more acid.

Relationships between Hydroxyproline-containing Proteins Secreted into the Cell Wall and Medium by Suspension-cultured Acer pseudoplatanus Cells.

The pathway of hydroxyproline-containing proteins to the cell wall, and to the growth medium in suspension-cultured Acer pseudoplatanus cells is traced by following the kinetics of the transfer of protein-bound (14)C-hydroxyproline into various fractions, and by comparing the hydroxyproline-arabinoside profiles of these fractions after alkaline hydrolysis.Hydroxyproline-rich protein passes directly from a membrane-bound compartment in the cytoplasm to the cell wall, not via an intermediate salt-soluble pool in the wall.There are at least three hydroxyproline-containing glycoproteins in the cell wall. One which possesses mono, tri, and tetraarabinoside side chains accounts for over 90% of the total hydroxyproline. This glycoprotein is "extensin."The hydroxyproline-containing proteins secreted into the medium have a glycosylation pattern markedly different from that of the major cell wall glycoprotein. It appears that there is little or no wall-like extensin in the medium.Approximately half of the protein-bound hydroxyproline secreted into the medium is linked to an arabinogalactan. This linkage is also found in a particulate wall protein precursor fraction from the cytoplasm, but only trace amounts can be detected in the cell wall.