The effect of granule microstructure on dissolution rate

The relationship between the microstructure of granules and their dissolution rate has been investigated. Granules consisting of mannitol primary particles and PVP aqueous binder have been prepared by top-spray fluid-bed granulation, and granules consisting of sucrose primary particles and PEG binder by in-situ melt fluid-bed granulation. Granule microstructure has been systematically varied by manipulating the primary particle size distribution and the binder content in each case. In both cases granule porosity was found to be a decreasing function of binder content and a minimum of porosity as function of the fine/coarse primary particle mixing ratio has been observed, in line with theoretical expectations. Granule microstructures have been analysed using X-ray computed micro-tomography and compared with three-dimensional “virtual granules” generated by a computer simulation of the agglomeration process. The dissolution rate of granules has then been measured. While porosity was found to have a strong effect on the dissolution rate of mannitol granules, the dissolution rate was found to be practically independent of porosity in the case of sucrose granules. The formulation-microstructure and microstructure-dissolution correlations established in course of this work are in line with previous computer simulation results and form part of a computer-aided granule design methodology.     

Composition limits in granulation with active component in the binder

The process of reactive granulation is considered. Sodium carbonate primary particles react with dodecyl‐benzenesulfonic acid droplets to form granules where the active component is an anionic surfactant formed by the reaction. The effect of primary particle size on the maximum binder/solids ratio was systematically investigated and found to be directly proportional to the specific surface area of the primary particles regardless of how this surface area was achieved—whether by monodisperse powders or bimodal powder mixtures. The effect of binder viscosity on the maximum binder capacity has shown a nontrivial behavior: while the maximum binder content increased with increasing binder viscosity for fine primary particles, the opposite trend was observed in the case of coarse primary particles. This behavior was explained by detailed studies of primary particle wetting and binder penetration into particle beds, as well as by microtomography analysis of the internal granule structure. © 2014 American Institute of Chemical Engineers AIChE J, 61: 395–406, 2015     

Computer simulation of granule microstructure formation

The diagenesis (porous microstructure evolution) of granules formed by a layering growth mechanism in a wet granulation process has been modelled. The model includes the packing of primary particles with a given size and shape distribution, and the deposition, spreading, and solidification of binder droplets within the growing granule. The dependence of granule porosity on the binder/solids ratio, primary particle size and morphology, and the rates of binder spreading and solidification has been investigated. The results are presented in the form of structure maps relating volume-averaged microstructure parameters with dimensionless groups including the ratio of droplet spreading and solidification times and the mean time between particle collisions. These graphs can guide the selection of process operating conditions or formulation ingredient properties required to obtain a particular granule microstructure.     

Multi-component granulation in a fast fluidized bed

The granulation of multi-component particles was conducted in a fast fluidized bed with an atomizing binder solution. The effects of gas velocity and binder droplet diameter on granulation rate, granule size distribution and granule composition were studied. The granulation rate and granule yield were determined by the balance between the agglomeration rate of feed particles and the disintegration rate of granules because there was no secondary granulation. With the increase in gas velocity and the reduction in binder droplet size, the agglomeration rate of feed particles decreased but the disintegration rate of granules increased, resulting in a reduced granule yield. Despite the larger fraction of small particles in the granules, the homogenous granulation of multi-component particles was achieved.     

Drop penetration time in heterogeneous powder beds

Wet granulation is a technique in which enlarged particles or ‘granules’ are produced from the coalescence of fine particles, with the intention of improving the powder properties. High shear granulators are often used to carry out the granulation process where the powder mass is agitated in a vessel by mechanical means while liquid is sprayed from above onto the powder bed surface. When the binder droplets impact the powder surface, the drop penetration time of the droplet into the powder is important for uniform binder dispersion and the prediction of the formation of granule nuclei from the nucleation map, which depends on the dimensionless spray flux. Previous studies on the drop penetration time were carried out on predominantly hydrophilic powder beds. Although this gives a good prediction of the nucleation behaviour in granulation, it does not reflect the condition where hydrophobic drugs are used in the formulation without surfactants. This paper aims to look at the effects of powder bed hydrophobicity on the drop penetration time.Single drop nucleation experiments using a syringe and a small powder bed were carried out on varying ratios of salicylic acid and lactose powders to study the kinetic of drop penetration. As expected, the drop penetration time increased as the proportion of hydrophobic component increased in the powder mixture. However, long drop penetration times were observed for low degrees of drug loading, showing that hydrophobicity strongly influences the drop penetration time. The wettability of the powder mixture also has a pronounced affect on the granule properties in which the hydrophobicity of the powder mixture is proportional to the granule strength and inversely proportional to the granule size. These findings have important implications in terms of the design of the granulation process where conditions of minimum spray flux or efficient mechanical forces are recommended to produce a more uniform granulation batch.     

The effect of powder size on induction behaviour and binder distribution during high shear melt agglomeration of calcium carbonate

Growth mechanisms in high shear mixer granulation were observed over a wide range of particle size and liquid-to-solid (L/S) ratio. The materials used were calcium carbonate (CaCO₃; size fractions in the range 1.5 to 85 μm) with a binder of polyethylene glycol 6000 (PEG 6k). The binder, solid at room temperature, was added by the “melt-in” method. A 10 L vertical-axis granulator was used, with a chopper and a four-bladed impeller.

The mean granule size and granule size distribution were measured at regular intervals during the agglomeration process by careful sampling and sieving. The uniformity of binder distribution among the granules was also measured.

The growth behaviours of each grade of primary particles were classified and compared. An induction type mechanism was observed with an initial period of slow growth in mean particle size that lasted 2 to 3 min (the induction period). This was followed by a short rapid growth phase lasting 1 to 2 min. The final stage was a plateau of more or less zero growth. Interestingly, the end of the induction period and the onset of rapid growth corresponded to a change in the granule size distribution from bimodal to monomodal and a similar change in the distribution of binder. Induction period growth rate tended to be lower for granules of finer particles, but these grew more rapidly during the rapid growth stage and produced larger granules than the coarser primary particles.

The liquid-to-solid (L/S) ratio had a significant effect on the growth rate during the rapid growth stage but a minor effect on the granule size distribution and binder distribution. Primary particle size had a significant effect on the final average size of granules, the growth rate during the rapid growth stage and the distribution of granule size and binder.     

Nucleation and growth in fluidised hot melt granulation

Fluidised hot melt granulation (FHMG) is a novel technology for granulation process in pharmaceutical industry, which has distinct advantages over other commercial techniques. The aim of this research was to investigate granulation and the effect of process parameters that may affect FHMG process. In this work, ballotini beads were used as the model particles and Lutrol® F 68 Poloxamer 188 was used as meltable solid binder. In order to determine the granulation and nucleation mechanism in this co-melt FHMG system, several parameters were investigated, such as binder content, particle size of binder and particle size and hydrophobicity of ballotini. These parameters were correlated to granule size distribution, mean granule size and granule shape. Furthermore, these experimental investigations were designed so that the coalescence model could be applied to the co-melt FHMG system. The analysis indicated that the non-inertial regime extends over a relatively short time period of < 60s, however this accounts for the majority of the particle size increase in the entire process. A decrease in the extent of granulation was induced by increasing the hydrophobicity of the ballotini, which was ascribed to a decrease in capillary pressure of the system.     

Particle growth mechanisms in fluidised bed granulation—I: The effect of process variables

Two types of product granule have been identified in an experimental study of batch fluidised bed granulation; agglomerates which consist of two or more, and usually several, initial particles; and layered granules, which consist of single primary particles with dried feed material adhering to the surface. Increasing the excess fluidising gas velocity, in the range U-U_mf = 0.15-0.525 m s^?1, resulted in decreased particle growth rates and, depending upon the binder material, a change in product morphology from agglomerates to layered granules. Similar changes resulted from increasing the mean size of the starting material. Thus, a mechanism of particle growth is proposed in which the strength of inter-particle bridges and the extent of fluid drag and inertial forces on particles determine the equilibrium granule form and size. However, if the initial particles are porous this mechanism may break down since liquid may enter intra-particle pores and be unavailable for the initial formation of liquid bonds.     

Behaviour of soft granules under compression: Effect of reactive and non-reactive nature of the binder on granule properties

Granulation is a process where primary powder particles are made to adhere to form multi-particle entities called granules and this is achieved by using a binder. The binders can be broadly classified into two categories viz. reactive (reacts with base powder) and non-reactive (does not react with the base powder). The effect of various parameters related to binder liquid (binder viscosity, addition rate, distribution over the bed etc.) on the mechanism of granulation and physical/mechanical properties of granules is well studied. However, comparison of physical and mechanical properties of granules made via reactive and non-reactive binder using the same base primary particles has not been reported. In this paper, granulation of sodium carbonate primary particles under reactive and non reactive conditions was studied. The mechanical properties of sodium carbonate granules were characterized using single granule compression measurements. The average single granule apparent strength of reactive granules was higher compared to non-reactive granules. It was observed that granules formed using non reactive binder were brittle and showed multiple breakages. However granules made using reactive binder showed single breakage followed by significant plastic flow. In addition, bulk granule compression measurements were also carried out. Known models of Heckel, Kawakita and Ludde, and Adams et al. (developed mainly for pharmaceutical and metal powders) were used to predict mechanical properties of soft detergent granules. The bulk granule compression measurements also showed that reactive granules have higher strength compared to non-reactive granules. However, the absolute values of granule strength obtained from the empirical models were lower than the granule strength obtained from single granule compression measurements.     

Effect of process parameters on the melt granulation of pharmaceutical powders

Co-melt granulation of lactose and PEG was investigated in a fluidised bed granulator. The effect of process parameters such as binder content and binder viscosity were correlated to granulation time and particle size distribution. The experimental data indicated that after initial nucleation the granulation mechanism was dependent upon binder content and binder viscosity. When the binder content was increased above 18% (w/w) de-fluidisation of the bed occurred and granulation moved to the slurry regime. As the process involved the melt granulation of relatively high molecular weight (6-20 k) and thus high viscosity PEG (500-19000 mPa s), it was found that binder viscosity had a significant affect on the granule growth mechanism. Granulation with a binder viscosity of 500 mPa s resulted in granule growth by coalescence, however, an increase in binder viscosity resulted in less coalescence and a lower granule growth rate. Furthermore, the granulation data were characterised by Stokes number analysis.     

Wet granule breakage in a breakage only high-hear mixer: Effect of formulation properties on breakage behaviour

Wet granule breakage can occur in the granulation process, particularly in granulators with high agitation forces, such as high-shear mixers. In this paper, the granule breakage is studied in a breakage only high-shear mixer. Granule pellets made from different formulations with precisely controlled porosity and binder saturation were placed in a high-shear mixer in which the bulk medium is a non-granulating cohesive sand mixture. After subjecting the pellets to different mixing time in the granulator, the numbers of whole pellets without breakage are counted and taken as a measure of granule breakage. The experimental results showed that binder saturation, binder viscosity and surface tension as well as the primary powder size have significant influence on granule breakage behaviour. It is postulated that granule breakage is closely related to the granule yield strength, which can be calculated from a simple equation which includes both the capillary and viscous force of the liquid bridges in the granule. The Stokes deformation number calculated from the impact velocity and the granule dynamic strength gives a good prediction of whether the granule of certain formulation will break or not. The model is completely based on the physical properties of the formulations such as binder viscosity, surface tension, binder saturation, granule porosity and particle size as well as particle shape.     

Particle growth mechanisms in fluidised bed granulation—II: Comparison of experimental data with growth models

Growth data from batch granulation experiments have been fitted to simple geometrical models. Layered granule growth approximates to concentric coating of core particles with binder, although the actual mechanism of growth is different. In the case of agglomeration, a relationship is established betwee mean granule size and binder content.     

Distribution and accessibility of binder in wet granules

The effect of primary particle morphology on the spatial distribution of binder in wet granules was investigated by numerical simulations. The shape factors of four commonly used pharmaceutical excipients - mannitol, lactose, microcrystalline cellulose, and calcium phosphate - were evaluated by digital image analysis and used for three-dimensional computer reconstruction of virtual particle populations. The formation of wet agglomerates was simulated by close random packing of primary particles and then finding the equilibrium distribution of a liquid binder in the pore space within the close packed structures, using the Volume of Fluid (VOF) method. The spatial distribution of binder in the computer-generated wet agglomerates was then analysed and the dependence of the fractional surface coverage by liquid on the overall binder/solids ratio was systematically obtained for different values of primary particle surface roughness. The obtained dependence was used to explain experimentally observed differences in the granulation kinetics of the four pharmaceutical excipients under otherwise identical conditions.     

Growth kinetics and mechanism of wet granulation in a laboratory-scale high shear mixer: Effect of initial polydispersity of particle size

The effect of initial polydispersity of particle size (unimodal versus bimodal distribution) and binder characteristics on the growth kinetics and mechanism of wet granulation was studied. Wet granulation of pharmaceutical powders with initial bimodal particle size distribution (PSD) presented growth kinetics consisting of two stages: fast growth followed by slow growth. The fast stage is controlled by the amount of binder and high probability of coalescence due to the collisions of small and large particles. The second stage is characterized by slow agglomeration of powder mixtures with water content 13.6% v/w, and slow breakage of powder mixtures with water content of 9.9% and 11.7% v/w. The wet granulation of powders with initial unimodal PSD exhibited slow growth kinetics consisting of one stage, since similar particle sizes do not promote agglomeration. The experimental results were better described by a population balance equation using a coalescence kernel that favors growth rate by collision between small and large particles. In general, the probability of a successful collision increased with higher size difference between particles, smaller particle size, and higher binder content.     

Wet granulation: the effect of shear on granule properties

This paper presents a study of the wet granulation of fine cosmetic particles using a high-shear mixer granulator on a given particle and binder system. The shear effect on granule properties is highlighted. The granules formed under different impeller speeds are divided into size classes and further examined in terms of porosity, friability and binder content.

The main result of this study is that, depending on operating conditions, the granulation of a fine powder with a given binding liquid can result in the formation of granules of very different characteristics in terms of size, porosity and friability. Mechanical energy brought to the granulation system is as important as the physicochemical characteristics of the powder–binder pair.     

Effects of process parameters on granules properties produced in a high shear granulator

Results of a study on the influence of process parameters such as impeller speed, granulation time and binder viscosity on granule strength and properties are reported. A high shear granulator (Cyclomix manufactured by Hosokawa Micron B.V., The Netherlands) has been used to produce granules. Calcium carbonate (Durcal) was used as feed powder and aqueous polyethylene glycol (PEG) as the binder. The dried granules have been analysed for their strength, density and size distribution. The results show that increasing the granulation time has a great affect on granules strength, until an optimum time has been reached. The underlying cause is an increase in granule density. Granules are consolidated more at higher impeller speeds. Moreover, the granule size distribution seems not to be affected significantly by an increase in impeller speed. Granules produced with high binder viscosity have a considerably lower strength, wide strength distribution due to poor dispersion of binder on the powder bed. Binder addition methods have showed no considerable effect on granule strength or on granule size distribution.     

Fluidized bed coating and granulation: influence of process-related variables and physicochemical properties on the growth kinetics

This study, which deals with the coating and granulation of solid particles by aqueous solutions of polymers or inorganic salts, aims to understand the effect of:

process-related variables such as the excess gas velocity, atomizer location, liquid flow rate and concentration, and atomizing air flow rate,

physicochemical-related variables such as the viscosity of solutions, wettability of the granulating liquid on solid particle surfaces, initial particle mean size, and porosity of the particles on the agglomeration kinetics of solid particles in a fluidized bed.

The results showed that for a given particle size, the fluidizing air velocity was the most important factor affecting the growth kinetics and the stability of the operation. An increase of the relative humidity, depending on the liquid flow rate as well as the air flow rate, favor agglomeration mechanism especially for values greater than 0.4. An increase in the particle initial size leads to an enhancement of the layering mechanism, especially for values greater than 300 μm.

The effect of the interfacial tension is investigated by adding different concentrations of a non-ionic surfactant to the binding solution. The effect of the contact angle is then studied using non-hydrophobic, partly hydrophobic, or totally hydrophobic particles. The growth of agglomerates appears to be favoured when the interfacial tension increases and the contact angle decreases. The viscosity of the solution has less effect than the interfacial parameters. The results show that the dominant forces in the granulation process are the capillary forces.     

Evaluation of the physical and mechanical properties of high drug load formulations: Wet granulation vs. novel foam granulation

The purpose of this study was to evaluate the influences of intrinsic drug mechanical properties and different granulation binder delivery processes on the physical and mechanical properties of high drug load granulations after wet granulation. Formulations (80% w/w) of acetaminophen (APAP), metformin and aspirin, which are brittle, viscoelastic, and ductile, respectively; were granulated by high-shear wet granulation. Two modes of binder delivery for wet granulation, either conventional or binder foam, were investigated. Particle size, surface area and pore size of the granulations were characterized. Compacts were prepared at a solid fraction of 0.9 under tri-axial decompression and Hiestand indices (worst-case bonding index (BI_w) and brittle fracture index (BFI)) of the compacts were determined. APAP formulations exhibited the smallest geometric mean particle sizes (d_g) and showed only slight differences in d_g values between the two granulation processes. Binder delivery mode affected mechanical properties of the granulated model drugs differently. Foam granulation appeared to enhance the granule plasticity for APAP while aspirin showed a mixed deformation mechanism based on both its high BI_w and high BFI values. The higher BI_w value for aspirin after foam granulation may be attributed to improved binder distribution among particles during granulation. On the other hand, conventional wet granulation improved the plasticity of metformin as measured by the higher BI_w and lower BFI values. Therefore, conventional wet granulation process conferred advantages in manufacturability and product quality for metformin; as compared to foam granulation which did not enhance plasticity for metformin. Based on this study, a wet granulation process can be selected based on knowledge of the intrinsic drug mechanical properties.     

Formation of hollow granules from liquid marbles: Small scale experiments

Research into formation of hollow granules from liquid marbles is an emerging field in hydrophobic granulation. A liquid marble is formed by a network of self-assembled hydrophobic powder around a droplet, and this paper investigates the conditions required for forming hollow granules from a liquid marble precursor.Single drops of fluid were produced using a syringe and placed onto loosely packed powder beds of hydrophobic powders. Liquid marbles formed from several powder/liquid combinations were dried at several conditions to investigate the drying conditions required for formation of a stable hollow granule.The formation of stable hollow granules was found to depend on drying temperature and binder concentration. For HPMC and PVP binder, formation of hollow granule is proportional to binder viscosity and for HPC binder, this relationship is constant. Different combinations of powder and binder at both drying temperatures - 60 °C and 100 °C - had mixed success rates in forming hollow granules, but generally the success rate was improved by using higher drying temperatures, smaller particles or higher viscosity binder fluids.     

粘结剂配比对干法制备ZrO2陶瓷轴承造粒粉性能的影响

为探究粘结剂中聚乙烯醇、聚乙二醇、羧甲基纤维素钠的配比对干法制备ZrO2陶瓷轴承造粒粉性能的影响,配制6份不同配比的粘结剂溶液,采用旋转流场式干法造粒机制备ZrO2陶瓷轴承造粒粉。搭建颗粒级配检测平台对造粒粉粒径分布进行分析,借助Carr流动性指数法分析造粒粉流动性。结果表明:聚乙烯醇对造粒粉颗粒级配及流动性影响最大,聚乙二醇次之,羧甲基纤维素钠最小。当粘结剂溶液中聚乙烯醇:聚乙二醇:羧甲基纤维素钠配比为3:6:1时,干法制备ZrO2陶瓷轴承造粒粉的有效颗粒占比为81.6%,流动性指数为81,造粒粉级配均匀、颗粒流动性好。