Pellet Size Distribution Research Articles

The Influence of Drug Solubility and Particle Size on the Pellet Formulation in a Rotoprocessor

ABSTRACTPellets containing drugs of different properties were prepared in a Rotoprocessor in order to study changes in the formulation process and resulting pellet characteristics. Diltiazem hydrochloride, diclofenac sodium, and theophylline were chosen as model drugs. Pellet size distribution, sphericity, density, hardness, friability, and repose angle were determined using standard methods. The amount of water as a wetting agent necessary for successful pellet formulation was observed for each sample and changed depending on drug solubility, concentration, and particle size. The pelletization of freely soluble diltiazem hydrochloride required 24.8–23.1% of the wetting agent and its amount decreased as the drug concentration increased. The demand for water in the formulation of theophylline pellets was 31.0–34.4% and it increased with increasing drug concentration. The pellet samples containing both drugs were easy to prepare. However, the cohesion of micronized diclofenac sodium particles negatively influenced both the pellet size distribution and the formulation process itself. When the drug concentration exceeded 40%, it was not possible to produce pellets of an appropriate size and the process was not reproducible.

Use of κ-carrageenan as alternative pelletisation aid to microcrystalline cellulose in extrusion/spheronisation. I. Influence of type and fraction of filler

Microcrystalline cellulose (MCC) is commonly used as an excipient in extrusion/spheronisation process. However, MCC owns several disadvantages as lack of disintegration and drug adsorption. Therefore, κ-carrageenan was investigated to substitute MCC in pelletising processes. Formulations with 20% of pelletisation aid (κ-carrageenan or MCC) and acetaminophen as a model drug have been produced. Different fillers (lactose, mannitol, maize starch and dicalciumphosphate dihydrate) at fractions of 0, 20, 40 and 80% were evaluated and the properties of the resulted pellets were determined (e.g. yield, aspect ratio, mean Feret diameter, 10% interval fraction, tensile strength and release profile). κ-Carrageenan has proven to be a suitable substitute as pellets with sufficient quality were produced. The pellet batches of different formulations were characterised by high yield, spherical pellet shape and narrow pellet size distribution. The distinguished behaviour between κ-carrageenan and MCC pellets was the lower tensile strength and the faster release of κ-carrageenan pellets. For the various types and fractions of fillers only minor effects to the pelletisation process and pellet properties were noticed. From the practical view these effects are neglectable indicating a robust formulation and process.

Model-based prediction of substrate conversion and protein synthesis and excretion in recombinant Aspergillus niger biopellets

Aspergillus niger grown as biopellets in a submerged culture has been used as an expression system for glucose oxidase (GOD). With regard to mass transfer, substrate utilization and the formation and excretion of the product GOD, the behavior of aggregated cells such as biopellets differed significantly from that of systems with suspended cells. A one-dimensional pellet model has been developed which is capable to describe the relevant processes in the pellet. Experimental results showed a phase with a highly dynamic pellet size distribution during the first 20 h of the cultivation. A stable number of pellets were usually found after this first period. In the model presented this initial process was described by assuming both suspended hyphae and a fixed number of pellets. The suspended hyphae were attached to the pellets and the substrate conversion and product formation was than described with the pellet model. The model predicted the production of GOD by A. niger in a bioreactor very well. The pellet density was identified as a key parameter which has to be provided as input parameter for the simulation runs. A sensitivity analysis with three different classes of pellet sizes showed that the influence of the final pellet size distribution on the simulation result was neglectable. On the other hand, it can be shown that the total pellet number, and thus the average pellet size was an important parameter. The pellet number influenced mainly the pellet surface area and, consequently, the turnover of substrate and formation and excretion of the product.

Properties of drug-containing spherical pellets produced by a hot-melt extrusion and spheronization process

The objectives of this study were to investigate the particle size distribution, morphology and dissolution properties of spherical pellets produced by hot-melt extrusion and spheronization and to compare the properties of hot-melt extruded pellets with beads manufactured by a traditional wet-mass extrusion and spheronization method. Spherical pellets were produced by hot-melt extrusion without the use of water or other solvents. A powder blend of theophylline, Eudragit® Preparation 4135 F, microcrystalline cellulose and polyethylene glycol 8000 was hot melt-extruded and the resulting composite rod was cut into cylindrical pellets. The pellets were then spheronized in a traditional spheronizer at an elevated temperature. The same powder blend was processed using conventional wet-mass techniques. Unlike wet-mass extruded pellets, pellets prepared from hot-melt extrusion displayed both a narrow particle size distribution and controlled drug release in dissolution media less than pH 7.4. Scanning electron microscopy, X-ray diffraction and porosity measurements were employed to explain the differences in drug release rates of theophylline from pellets produced by the two processing techniques. Theophylline release from the hot-melt extruded pellets was described using the Higuchi diffusion model, and drug release rates from wet-granulated and melt-extruded pellets did not change after post-processing thermal treatment.

Influence of Naineris laevigata (Polychaeta: Orbiniidae) on vertical grain size distribution, and dinoflagellate resting stages in the sediment

Short-term experiments were performed with the polychaete Naineris laevigata Grube, a conveyor-belt deposit feeder, to evaluate: the daily sediment reworking rate, the influence of the activity of this burrowing worm on the vertical redistribution of the sediment and dinoflagellate cysts. We also tested the germination success of cysts after their passage through the gut of the polychaete. Vertical particle distribution was studied in small aquaria with and without worms and with an initially layered sediment. After 30 days, sediment cores were collected in controls and treatments at 3 different depths (upper, intermediate and deep) and the diameter of 100 particles from each depth was measured to obtain the size-frequency distribution. The burrowing activity of 3 worms may completely mix a pre-existent layering within 30 days. The translocation of a mud layer from 4 cm depth towards the surface was observed. The mud layer deposited on the surface by the end of the experiment was at least 1 cm thick. Daily average production of faecal pellets was 0.443±0.032 g per worm. From the first day of the experiment, the particle size distribution of the faecal pellets released at the surface revealed the presence of sediment and cysts originating from underlying layers. Tests showed that the germination percentage of the cysts significantly diminished after passage through the guts of the worms. Our results indicate that N. laevigata is an effective vertical mixer of sediment and plays a role in the vertical transport and germination success of resting stages.

Direct pelletization in a rotary processor controlled by torque measurements. II: effects of changes in the content of microcrystalline cellulose.

In the present study we investigated the effect of changes in the content of microcrystalline cellulose (MCC) on a direct pelletization process in a rotary processor in which the liquid addition was terminated once a certain increase in torque was produced. Nine different mixtures of MCC and lactose with MCC contents varying from 10% to 100% (w/w) were pelletized using 6 different torque increase levels, and the changes in pellet characteristics were investigated. The pellet characteristics investigated were pellet shape, size, and size distribution as well as the water content of the pellets at the end of liquid addition. To produce spherical agglomerates with suitable characteristics in a reproducible way, a content of at least 20% (w/w) MCC was found necessary. Linear correlations were found between the MCC content and the water content and between the torque increase and the water content, showing that the torque increase is suitable to control the process. A higher torque increase or a higher MCC content was found to increase the water content independently of each other.

Optimization of the hydroxylation of 2-cyclopentylbenzoxazole with Cunninghamella blakesleeana DSMZ 1906.

Biohydroxylation of 2-cyclopentyl-1,3-benzoxazole with the filamentous fungus Cunninghamella blakesleeana DSMZ 1906 was studied in a 15-l stirred tank reactor. The aim of the work was to avoid substrate limitation through sub-optimal mixing by formation of pellets with a uniform pellet size distribution of 250-500 microm, obtained at an inoculum concentration of 10(7) spores ml(-1) and an agitation rate of 390 rpm. Due to the high toxicity of the educt, 2-cyclopentyl-1,3-benzoxazole, on the fungus, the medium composition, the time of educt addition, and the educt starting concentration were optimized to reach high educt tolerance and hydroxylation activity. A good maintenance of biotransformation capacity was obtained without excessive loss of activity of the biocatalyst by addition of 30 mg 2-cyclopentyl-1,3-benzoxazole/g biomass (cell dry mass) during the stationary phase in a medium which was optimized in batch fermentations with experimental designs. An increase in product yield and quality (enantiomeric excess) was achieved by developing feeding strategies combining the educt and medium components. The resulting fermentation broth contained 450 mg l(-1) of the product (1S,3S)-3-(benz-1,3-oxazol-2-yl)cyclopentan-1-ol with an enantiomeric excess of 95%, which represents a 48% increase over former reported results.

Study of the melt pelletization process focusing on the micromeritic property of pellets.

Melt pelletization of lactose 450 M was carried out in an 8-l high shear mixer using PEG 3000 as the meltable binder. The pore size and size distribution of the melt pellets were determined using mercury intrusion porosimetry. The pore size distribution of melt pellets was found to be bimodal. With a higher binder concentration, post-melt impeller speed or longer post-melt processing time, the fraction of large pores in the agglomerates was reduced but the tendency of the agglomerates to develop sub-micron pores increased. The extent of formation of large pores was dependent on the interplay between the inter-particle distance of lactose particles and the contraction property of molten binder. High process temperature was associated with a greater amount of water loss from the melt agglomerates. The water vapor liberated from the lactose particles, was trapped in the molten PEG during the pelletization process. The formation of sub-micron pores was a result of escape of this water vapor on solidification of the molten PEG as well as agglomerate densification. The quantity of sub-micron pores produced was found to be related to the level of water loss. The melt agglomeration gave rise to large agglomerates when long post-melt processing time, high post-melt impeller speed or binder concentration was used.

Melt pelletisation of a hygroscopic drug in a high shear mixer: Part 1. Influence of process variables

The applicability of a high shear mixer for melt pelletisation of binary mixtures of sodium valproate and glycerol monostearate was investigated. The effects of binder concentration, impeller speed, jacket temperature and massing time on mean pellet size and size distribution were examined in a 2 4-factorial design. Binder concentration and impeller speed were found to be the most important variables influencing the mean granule size and size distribution. An increase in each of those accelerated the granule growth. Due to the solubility of the drug in the molten binder very low amounts of binder were necessary for the formation of pellets. The modified high shear mixer was found to be suitable for batch sizes of 1–4 kg; granule growth was delayed with increasing load. A common pellet growth pattern, which can be divided into three phases, was derived and confirmed from all trials. The process was monitored by means of a torque measuring system. The torque–time curve can be used to detect the beginning of the destruction phase.

Preparation of Ultrafine Monodispersed Indium−Tin Oxide Particles in AOT-Based Reverse Microemulsions as Nanoreactors

Monodispersed ultrafine indium−tin oxide (ITO) particles were prepared in AOT-based reverse microemulsions with indium nitrate and tin chloride dissolved in water droplets. The particle size distribution, calcination rate, chemical composition, and electrical resistivity of pellets manufactured with particles were measured and compared with analogous measurements of particles formed by bulk precipitation method. ITO particles formed in microemulsions showed a narrower size distribution, faster calcination rate, and lower electrical resistivity. It was also confirmed that tin molecules are doped into the indium oxide homogeneously rather than forming a discrete tin oxide domain in indium−tin oxide particles formed in microemulsions.

Effects of Physical Properties of PEG 6000 on Pellets Produced by Melt Pelletization

This study examined the effects of polyethylene glycol (PEG) binders of different physical forms and from different commercial sources on size and size distribution of pellets produced. The meltable binders used were PEG 6000 in the form of flakes, and coarse and fine powders, and melt pelletization using lactose 450 M was carried out in an 8-liter high-shear mixer. Binder particle size, molecular weight, tack, and viscosity were determined. The results showed that the size and size distribution of the pellets obtained could not be explained by the binder particle size. The size and size distribution of the pellets were related to the tack and viscosity of the molten binders. PEGs used were labeled as the same nominal molecular weight grade, although their determined molecular weights could be quite different. Differences in tack and viscosity of the molten binders were associated with determined molecular weight of the binders. The melt pelletization process is sensitive to tack and viscosity of the molten binders. When different PEG brands of the same nominal molecular weight or different batches of the same brand are used in melt pelletization, it is important to characterize the tack and viscosity of the binders used. The effects of the physical form of binders on the pellet quality appear to be less important when compared to the influences of tack and viscosity of the molten binder.

Effect of Off-Bottom Clearance on Properties of Pellets Produced by Melt Pelletization

ABSTRACTThis study examines the influence of off-bottom clearance on size and size distribution of pellets produced during melt pelletization at different postmelt impeller speeds and binder concentrations using lactose and polyethylene glycol. Melt pelletization of lactose powder 450 M in an 8-liter high-shear mixer, the floor of which was made of polytetrafluoroethylene (PTFE), was carried out with polyethylene glycol 3000 as the meltable binder. Erosion of the PTFE floor of the mixer occurred with time of use and this caused a change in the off-bottom clearance. The findings showed that with a wider clearance, the size distribution of pellets was wider and pellets were much larger. These changes were the results of changes in the mixing intensity and impact frequency of the mass in relation to the eddies formed within the off-bottom clearance. The changes were not associated with the reduction in the circulating material load by entrapment into the off-bottom clearance. In the melt pelletization process, the quality of product was higher if the clearance was kept to a minimum. The off-bottom clearance was best measured at the beginning of each pelletization run because the PTFE floor of the mixer was prone to erosion.

Growth mechanisms of high-shear pelletisation

Two high-shear mixers, Gral 10 and Gral 25, were used to prepare pellets of microcrystalline cellulose and lactose, using water as binder liquid. Growth of pellets was investigated by measuring the pellet size distribution during the process. On the basis of the experiments the destructive nucleation growth mechanism was defined. Pelletisation was started with the formation of large primary nuclei. Small secondary nuclei were formed due to break-up of the primary nuclei. This nucleation process could be described by the comparison of the theoretical tensile strength of the nuclei and the dynamic impact pressure. Due to densification, the secondary nuclei became stronger and growth proceeded exponentially by coalescence. During the kneading stage, net growth was diminished until a steady state was observed. The mean pellet size did not change during the final stage of the kneading phase which resulted in a well-defined product.

The Temporal Variation of Flocs and Fecal Pellets in a Tidal Channel

Fine-grained sediment transported in suspension in a tidal channel consists of single grains, flocculated material and fecal pellets. The temporal variation during the tidal period in settling velocities of flocs, as well as the number and size of fecal pellets, is influenced by several parameters; current velocity and suspended-sediment concentration are shown to be the most important. The equivalent settling diameters of the suspended matter are almost constant close to the water surface, whereas at the bottom, they vary following the variation in suspended-sediment concentrations. The maximum number of fecal pellets are found around low water slack, when the tidal flats adjacent to the channel are being drained. After dispersion, the grain size distribution of both flocculated material and fecal pellets is almost identical, with a median diameter of 5 μm.

The Influence of Five Selected Processing and Formulation Variables on the Particle Size, Particle Size Distribution, and Friability of Pellets Produced in a Rotary Processor

A factorial-designed study has been performed to investigate the effect of two formulation variables and three processing variables on size, size distribution, and friability of pellets made in a rotary processor by the wet granulation technique. The first are the microcrystalline cellulose content and the ratio of the amount of added water to the amount of microcrystalline cellulose in the powder mixture; the latter are the rotor speed, the spheronization time after water addition, and the water addition rate. Both formulation variables and the three processing variables have a major influence on pellet size and percentage loss in weight in the friability test. With the exception of the spheronization time, increasing an independent variable results in a wider size distribution. The wet granulation technique in the rotary processor has been judged to be a critical technique. However, if all variables are fully controlled, rather good reproducibility can be obtained

Control of pellet morphology of filamentous fungi in fluidized bed bioreactors by means of a pulsing flow. Application to Aspergillus niger and Phanerochaete chrysosporium

The application of a pulsing flow to fluidized-bed bioreactors in order to control pellet morphology of filamentous fungi was investigated. The operation at an optimum pulsation frequency allowed two effects: a narrower pellet size distribution which improves fluidization quality, and an enhanced production of citric acid by Aspergillus niger and manganese peroxidase by Phanerochaete chrysosporium. In the case of A. niger, the pellet diameter corresponding to the pulsed system operated at 0.35 s −1 was kept between 3.3 ± 0.1 mm after 22 days of operation; however, in the nonpulsed bioreactor which was operative for only 11 days, pellets with a diameter of 6.7 ± 0.3 mm were produced. Similar results were obtained in the case of P. chrysosporium, since with a pulsing frequency of 0.0625 s −1, a pellet diameter of 2.1 ± 0.4 mm after 34 days of operation was maintained. On the contrary, the system without pulsation presented great conglomerates of mycelia with an average diameter of 3 cm surrounded by free pellets with a diameter distribution of 2.75 ± 0.5 mm. The nonpulsed bioreactor was only operative for 14 days. Both citric acid and manganese peroxidase production attained higher values and were maintained longer in the pulsed bioreactor.

Experimental verification of a mathematical model for pelleted growth of Streptomyces coelicolor A3(2) in submerged batch culture

A published mathematical model for growth of pellets of filamentous microorganisms has been tested by comparison of model predictions with experimental data on growth of Streptomyces coelicolor in liquid batch culture. The original model considered the classification of pellets into a range of size classes. Growth resulted in movement of pellets to classes of increasing size, while shear forces produced mycelial fragments which entered the smallest size class, from which they grew to form further pellets. This model did not correctly describe changes in pellet size distributions during growth and was therefore modified in two ways. In the first, new pellets were assumed to be formed by the break-up, by shear forces, of existing pellets into two pellets of equal size, rather than removal of small hyphal fragments from the pellet surface. The second modification assumed that the outer shell of active mycelial biomass had a density less than 1 g cm-3 and that hyphal density within this shell decreased with distance from the pellet centre. The modified model generated predictions which agreed closely with experimental data on biomass concentration, pellet size distribution, pellet number and pellet radius during batch growth, thereby supporting the assumptions on which the model was based. The model did not accurately describe final biomass concentration, through lack of consideration of autolysis of mycelia at the centre of larger pellets in which growth was limited by diffusion of nutrients. Attempts to incorporate autolysis into the model improved prediction of biomass concentration but were not based on sound biological assumptions and increased the complexity of the model. Further experimental work is required for accurate description of the effects of autolysis on pellet growth.

Experimental verification of a mathematical model for pelleted growth of Streptomyces coelicolor A3(2) in submerged batch culture.

A published mathematical model for growth of pellets of filamentous microorganisms has been tested by comparison of model predictions with experimental data on growth of Streptomyces coelicolor in liquid batch culture. The original model considered the classification of pellets into a range of size classes. Growth resulted in movement of pellets to classes of increasing size, while shear forces produced mycelial fragments which entered the smallest size class, from which they grew to form further pellets. This model did not correctly describe changes in pellet size distributions during growth and was therefore modified in two ways. In the first, new pellets were assumed to be formed by the break-up, by shear forces, of existing pellets into two pellets of equal size, rather than removal of small hyphal fragments from the pellet surface. The second modification assumed that the outer shell of active mycelial biomass had a density less than 1 g cm-3 and that hyphal density within this shell decreased with distance from the pellet centre. The modified model generated predictions which agreed closely with experimental data on biomass concentration, pellet size distribution, pellet number and pellet radius during batch growth, thereby supporting the assumptions on which the model was based. The model did not accurately describe final biomass concentration, through lack of consideration of autolysis of mycelia at the centre of larger pellets in which growth was limited by diffusion of nutrients. Attempts to incorporate autolysis into the model improved prediction of biomass concentration but were not based on sound biological assumptions and increased the complexity of the model. Further experimental work is required for accurate description of the effects of autolysis on pellet growth.

Improvement of the material motion in a rotary processor.

The purpose of this paper is to reject or to confirm the hypothesis that the influence of the water addition rate on the size and size distribution of pellets is caused by insufficient spreading of the added water at higher water addition rates. To overcome insufficient spreading of the added water, the agitation in the rotary processor is intensified by improving the spiral, rope-like movement by means of two baffles and a permanent PTFE coating, and by installing a chopper. Improvement of the spiral, rope-like movement moderates the influence of the water addition rate on the pellet size. The chopper has no significant influence on pellet size, pellet size distribution, or percentage of agglomerates for the pellets, which are investigated in this study. Furthermore, the implementation of the technical modifications does not influence the dissolution characteristics of the pellets directly. It is therefore concluded that the water added is well spread over the mass by ensuring an optimal spiral, rope-like movement, so that incorporation of a chopper is superfluous. The remaining influence of the water addition rate on the pellet size can most probably be explained by differences in processing time, resulting in different volumes of air capable of extracting water from the powder mass.

A mathematical model for the growth of mycelial pellet populations

In liquid culture, filamentous organisms often grow in the form of pellets. Growth result in an increase in radius, whereas shear forces result in release of hyphal fragments which act as centers for further pellet growth and development. A previously published model for pellet growth of filamentous microorganisms has been examined and is found to be unstable for certain parameter values. This instability has been identified as being due to inaccuracies in estimating the numbers of fragments which seed the pellet population. A revised model has been formulated, based on similar premises, but adopting a finite element approach. This considers the population of pellets to be distributed in a range of size classes. Growth results in movement to classes of increasing pellet size, while fragments enter the smallest size class, from which they grow to form further pellets. The revised model is stable and predicts changes in the distribution of pellet sizes within a population growing in liquid batch culture. It considers pellet growth and death, with fragmentation providing new centers of growth within the pellet population, and predicts the effects of shear forces on pellet growth and size distribution. Predictions of pellet size distributions are tested using previously published data on the growth of fungal pellets and further predictions are generated which are suitable for experimental testing using cultures of filamentous fungi or actinomycetes.