Evolution and structure of drying material bridges of pharmaceutical excipients: studies on a microscope slide

An experimental procedure was developed to study directly the process by which liquid bridges between small particles in a granule form and solidify. The evolution of saturated solutions of such pharmaceutical excipients as lactose and mannitol in a liquid bridge was studied on a system situated on a microscope slide. Solidification and crystallization kinetics and phase composition during and immediately following bridge formation were observed directly. It was shown that bridges on the microscope slide and in the granule behave very much the same regardless of the different length and diffusion-scales of the two systems.We found that solid bridge formation takes place in several consecutive but distinct steps. In the case of lactose, considerable shrinkage of the initial liquid bridge takes place prior to the onset of crystallization. Further bridge solidification at ambient conditions occurs via simultaneous crystallization and vitrification within minutes. As a result, a “solid” bridge usually contains both a crystalline and a non-crystalline phase, the crystalline phase being predominately α-lactose monohydrate. Most of the non-crystalline phase eventually converts to crystalline β-lactose but the process may take many hours or even days. Results for this process are compared for samples obtained from different manufacturers of commercially available lactose. In the case of mannitol, different polymorphic forms crystallize as the drying/crystallization process progresses. A formed “solid” bridge usually contains several polymorphs of mannitol. The relevance of the behavior of the two model systems (pure lactose and pure mannitol) to a real granulation and tabletting process is discussed.     

Cooling and Solidification of Melted Drops in an Immiscible Cooling Medium

The cooling and solidification of melted drops during their movement in an immiscible cooling medium is widely employed for granulation in the chemical industry, and a study of these processes to provides a basis for the design of the granulation tower height and the temperature of the cooling medium is reported. A physical model of the cooling and solidification of the drop is established and the numerical calculation is performed. The influences of the key factors in the solidification, i.e., Bi number, drop diameter, temperature of the cooling medium, etc. are presented. The cooling and solidification during wax granulation in a water‐cooling tower and during urea granulation in an air‐cooling tower (spraying tower) are described in detail. Characteristics of the solidification and temperature distribution within the particle at different times are shown. The model and calculations can be used for structure design of the granulation tower and optimization of the operation parameters.     

Optimal control and operation of drum granulation processes

Process optimisation and optimal control of batch and continuous drum granulation processes are studied in this paper. The main focus of the current research has been: (i) construction of optimisation and control relevant, population balance models through the incorporation of moisture content, drum rotation rate and bed depth into the coalescence kernels; (ii) investigation of optimal operational conditions using constrained optimisation techniques; (iii) development of optimal control algorithms based on discretized population balance equations; and (iv) comprehensive simulation studies on optimal control of both batch and continuous granulation processes. The objective of steady state optimisation is to minimise the recycle rate with minimum cost for continuous processes. It has been identified that the drum rotation-rate, bed depth (material charge), and moisture content of solids are practical decision (design) parameters for system optimisation. The objective for the optimal control of batch granulation processes is to maximize the mass of product-sized particles with minimum time and binder consumption. The objective for the optimal control of the continuous process is to drive the process from one steady state to another in a minimum time with minimum binder consumption, which is also known as the state-driving problem. It has been known for some time that the binder spray-rate is the most effective control (manipulative) variable. Although other possible manipulative variables, such as feed flow-rate and additional powder flow-rate have been investigated in the complete research project, only the single input problem with the binder spray rate as the manipulative variable is addressed in the paper to demonstrate the methodology. It can be shown from simulation results that the proposed models are suitable for control and optimisation studies, and the optimisation algorithms connected with either steady state or dynamic models are successful for the determination of optimal operational conditions and dynamic trajectories with good convergence properties.     

Effect of RE on Granulation of Eutectic Carbide in Ledeburite Steel

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A novel nucleation apparatus for regime separated granulation

A novel nucleation apparatus is presented for the production of narrow sized nuclei from various powder and binder liquid combinations. Mono-sized binder liquid droplets are produced by a specially designed mono-disperse droplet generator. The droplet generator is positioned above a conveyor belt, transporting a powder bed through the spray zone of the droplet generator. By nucleating powder on a conveyer belt, the nucleation mechanism is completely separated from all other granulation mechanisms due to the lack of relative motion between primary particles and/or formed nuclei. Nucleation tests were performed using chalcopyrite and limestone powders with water as the binder liquid. At all operating conditions, the formed nuclei were found to originate from multiplicities of drops that merged on the powder bed surface. Investigation of the dynamics of nuclei formation showed that powder-binder liquid combinations with fast penetration dynamics result in less variation in the number of droplets from which nuclei originate. Smaller and more narrowly distributed nuclei were also achieved by increasing powder speed through the spray zone.     

Flow patterns in granulating systems

Particle flow patterns were investigated for wet granulation and dry powder mixing in ploughshare mixers using Positron Emission Particle Tracking (PEPT). In a 4-l mixer, calcium carbonate with mean size 45 μm was granulated using a 50 wt.% solution of glycerol and water as binding fluid, and particle movement was followed using a 600-μm calcium hydroxy-phosphate tracer particle. In a 20-l mixer, dry powder flow was studied using a 600-μm resin bead tracer particle to simulate the bulk polypropylene powder with mean size 600 μm. Important differences were seen between particle flow patterns for wet and dry systems. Particle speed relative to blade speed was lower in the wet system than in the dry system, with the ratios of average particle speed to blade tip speed for all experiments in the range 0.01–0.25. In the axial plane, the same particle motion was observed around each blade; this provides a significant advance for modelling flow in ploughshare mixers. For the future, a detailed understanding of the local velocity, acceleration and density variations around a plough blade will reveal the effects of flow patterns in granulating systems on the resultant distribution of granular product attributes such as size, density and strength.     

Population balances for particulate processes—a volume approach

Population balance models have been used in chemical engineering since the 1960s and have evolved to become the most important tools for design and control of particulate processes. In this paper we show that the intrinsic particle parameter that determines changes in the process and should thus be included in the population balance is the particle volume. The basic population that is modeled should be the mass distribution, or the volume distribution if the density is constant. The population balance thus describes the change of the volume distribution of volume with time. Furthermore, we suggest that the “birth” and “death” terms that are often used to describe discrete events in particulate processes can almost always be replaced by a rate of change term.To design and control existing and future processes, a multi-dimensional population balance model is required. We propose a volume-based model in which the particle properties that are modeled are the volumes of solid, liquid, and air, respectively. In the most general case the model will consist of a properties vector and a distribution tensor. Depending on the complexity of the process, one or more of the properties may be omitted from the model. This is shown in three examples of increasing complexity: comminution, sintering, and granulation.     

Evaluating spray gelation and spray freeze drying as the granulation method to prepare oral tablets of amorphous drug nanoplex

Amorphous drug nanoplex represents one of the most promising solubility enhancement strategies of poorly-soluble drugs. Solubility enhancement capability of nanoplex hitherto has been demonstrated for nanoplex suspension and lyophilized/spray-dried nanoplex, but not for its oral tablets. Using ciprofloxacin as the model poorly-soluble drug, we investigated spray gelation (SG) of alginate and spray freeze drying (SFD) with cryoprotective mannitol, as the nanoplex’s granulation methods. Both granules were evaluated in terms of their morphology, physical form, flowability, drug content, preparation yield, dissolution profile, drug solubility enhancement, and storage stability. Subsequently, tablets of the granules were prepared and characterized in terms of their drug content uniformity, weight variation, friability, hardness, dissolution profile, and solubility enhancement. The results showed that nanoplex in SG granules was embedded in dense amorphous alginate matrix, while nanoplex in SFD granules was dispersed in porous crystalline mannitol particles. Despite their distinct morphology, physical form, and dissolution profile, the two granules exhibited similar drug solubility enhancements. Both granules were readily compacted into tablets with minimal changes in their dissolution and solubility enhancement after tableting. The present work demonstrated SG and SFD as viable granulation methods of nanoplex, with SG granules exhibiting superior flowability, stability, but lower yield.     

Positive approximation and converse approximation in interval-valued fuzzy rough sets

Methods of fuzzy rule extraction based on rough set theory are rarely reported in incomplete interval-valued fuzzy information systems. Thus, this paper deals with such systems. Instead of obtaining rules by attribute reduction, which may have a negative effect on inducting good rules, the objective of this paper is to extract rules without computing attribute reducts. The data completeness of missing attribute values is first presented. Positive and converse approximations in interval-valued fuzzy rough sets are then defined, and their important properties are discussed. Two algorithms based on positive and converse approximations, namely, mine rules based on the positive approximation (MRBPA) and mine rules based on the converse approximation (MRBCA), are proposed for rule extraction. The two algorithms are evaluated by several data sets from the UC Irvine Machine Learning Repository. The experimental results show that MRBPA and MRBCA achieve better classification performances than the method based on attribute reduction.     

Valorization of steel slag by a combined carbonation and granulation treatment

This work reports the results of a combined accelerated carbonation and wet granulation treatment applied to Basic Oxygen Furnace (BOF) steel slag with the aim of producing secondary aggregates for civil engineering applications and of storing CO₂ in a solid and thermodynamically stable form. The tests were carried out in a laboratory scale granulation device equipped with a lid and CO₂ feeding system. In each test, humidified slag (liquid/solid ratio of 0.12 l/kg) was treated for reaction times varying between 30 and 120 min under either atmospheric air or 100% CO₂. Under both conditions, the particle size of the treatment product was observed to increase progressively with reaction time; specifically, the d₅₀ values obtained for the products of the combined granulation and carbonation treatment increased from 0.4 mm to 4 mm after 30 min and to 10 mm after 120 min. Significant CO₂ uptake values (between 120 and 144 g CO₂/kg) were measured even after short reaction times for granules with diameters below 10 mm and for the coarser particle size fractions after reaction times of 90 min. The density, mineralogical composition and leaching behavior of the obtained granules were also investigated, showing that the combined granulation–carbonation process may be a promising option for BOF slag valorization, particularly in terms of decreasing the Ca hydroxide content of the slag. Another interesting finding was that the leaching behavior of the product of the combined treatment appeared to be significantly modified with respect to that of the untreated slag only for coarse uncrushed granules, an indication that the carbonation reaction occurs mainly on the outer layer of the formed granules.