Extent Of Granulation Research Articles

Twin screw granulation: A simpler re-derivation of quantifying fill level.

The fill level is defined as the volume occupied by the powder and granules inside the twin-screw granulator in proportion to the maximum barrel channel void 'free' volume. In literature, the fill level is one of the key factors that determine the final granule properties as it relies on several factors such as the screw speed, screw element geometry, mass flow rate and barrel length. However, quantitative prediction of the fill level in twin-screw granulation (TSG) is still a developing area, which is required to enable effective development of process design space, to yield a product with desired quality attributes for all process scale levels (small to large equipment). In this study, a simple geometrical model is presented that predicts the barrel channel fill level in TSG. This model relates the volumetric flow rate to the forward volumetric conveying rate of the screws when they advance in the axial direction. Experimentation was conducted to validate the model by analytically measuring mass hold-up, the amount of material remaining in the barrel after steady state was reached, as the fill level is proportional to mass hold-up. Furthermore, the trends in the extent of granulation with the proposed model were investigated. Good agreement was found between the proposed fill level model and the mass hold-up for various screw elements, therefore the model provides a more practical measure of the fill level in TSG.

Improving liquid distribution by reducing dimensionless spray flux in wet granulation—A pharmaceutical manufacturing case study

Controlling liquid distribution in a wet granulation process is critical to maintaining control of both nucleation and growth, as highly saturated patches created by uneven liquid distribution will have a much higher growth rate and may form large “balls”. The size of these balls depends on the granulator scale, but in full-scale pharmaceutical manufacturing these lumps are commonly 2–3 cm in diameter, but may even be larger. The presence of a significant quantity of “balls” frequently results in downstream problems in drying, milling, compression and final product attributes. This paper presents a case study of attempting to improve the liquid distribution during manufacturing of an existing wet-granulated product with a long history of “balls”. The flowrate and spray area of the original nozzle were measured, and a simple estimation of the drop size was obtained by a high-speed photograph and image analysis. The powder surface velocity in a 400L Diosna was measured using a high-speed camera and a simple image analysis technique for several batches using different lots of the drug. Since the manufacturing process was validated and filed, the simplest process change that could be made to attempt to reduce the spray flux and improve liquid distribution was to find a new nozzle. A new nozzle was selected and implemented in a full-scale production batch and the results are compared with the original nozzle conditions. Reducing spray flux by changing the nozzle actually increased ball formation, contrary to what was expected. For products in the growth and/or induction regimes, increasing the efficiency of liquid distribution may mean that less total liquid is required to be added to achieve the same extent of granulation. Improving liquid distribution without also reducing the total volume will result in a shorter induction period and/or a higher growth rate and larger granule size. The study found that the major contribution to batch-to-batch variation in spray flux was the large variations in powder surface velocity for each batch, which is presumably caused by changes in the physical properties of each lot of drug. This has not been reported previously and has important implications for understanding the causes of variability in liquid distribution and granule/ball size in full-scale production of wet-granulated pharmaceutical products.

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.

Co-melt fluidised bed granulation of pharmaceutical powders: Improvements in drug bioavailability

This study investigates the use of co-melt fluidised bed granulation for the agglomeration of model pharmaceutical powders, namely, lactose mono-hydrate, PEG 10000, poly-vinyl pyrolidone and ibuprofen as a model drug. Granulation within the co-melt system was found to follow a nucleation—steady growth—coating regime profile. Using high molecular weight PEG binder, the granulation mechanism and thus the extent of granulation was found to be significantly influenced by binder viscosity. The compression properties of the granulate within the hot fluidised bed were correlated using a novel high temperature experimental procedure. It was found that the fracture stress and fractural modulus of the materials under hot processing conditions were orders of magnitude lower than those measured under ambient conditions. A range of particle velocities within the granulator were considered based on theoretical models. After an initial period of nucleation, the Stokes deformation number analysis indicated that only velocities within the high shear region of the fluidised bed were sufficient to promote significant granule deformation and therefore, coalescence. The data also indicated that larger granules de-fluidised preventing agglomeration by coalescence. Furthermore, experimental data indicated that dissipation of the viscous molten binder to the surface was the most important factor in the latter stages of the granulation process. From a pharmaceutical perspective the inclusion of the model drug, ibuprofen, combined with PVP in the co-melt process proved to be highly significant. It was found that using DSC analysis on the formulations that the decrease in the heat of fusion associated with the melting of ibuprofen within the FHMG systems may be attributed to interaction between PVP and ibuprofen through inter-molecular hydrogen bonding. This interaction decreases the crystallinity of ibuprofen and facilitates solubilisation and bioavailability within the solid matrix.

Quantifying liquid coverage and powder flux in high-shear granulators

A key aspect to high-shear wet granulation is the coverage of binding fluid as it first comes into contact with the surface of a powder bed. Quantifying the parameters that determine liquid coverage with respect to powder flux could improve the ability to rationally characterize and scale wet granulation processes. In this work, the surface velocity of a powder bed was measured during wet granulation in high-shear mixers (Aeromatic-Fielder) ranging from lab (25 l) to pilot (300 l) scale. High-speed video analysis revealed that surface velocity is strongly dependent on impeller speed, mixer scale, fill level, and extent of granulation. Surface velocity results were coupled with the dimensionless spray flux concept reported by Litster et al. [Powder Technol. 114 (2001) 32] to quantify liquid coverage relative to powder flux for operating conditions commonly used to granulate pharmaceutical powder blends. Dimensionless spray flux calculations suggest that granule nucleation in high-shear mixers does not take place in the drop-controlled regime. The density of spray drops at the surface of the powder bed is sufficiently high to cause a significant amount of drop overlap, thereby hindering the formation of nuclei from individual spray drops. Dimensionless spray flux calculations predict an approximate 2.5-fold increase in liquid coverage upon scaling a standard high-shear wet granulation process from 25 to 300 l. The use of multiple spray nozzles could potentially minimize differences in liquid coverage between scales. Practical limitations of the dimensionless spray flux concept are discussed and an empirically modified version of the original spray flux equation is presented.

Modeling agglomeration processes in fluid‐bed granulation

AbstractMany agrochemicals are formulated as water dispersive granules through agglomeration, beginning with a fine powder (∼1 μm) and ending with granules on the order of 500 μm. Powders are charged into a granulation system with a liquid binding agent, and granules are subsequently grown to an appropriate size. Granulation in fluid beds is presented using a mass conserving discretized population balance equation. Coalesce kernels governing the rate and extent of granulation are assumed dependent on the Stokes number, which is indirectly linked to important process variables (air and binder flow rate, bed charge, bed geometry) such that the physical processes governing particle coalescence and rebound are correlated to process variables. A new coalescence kernel is proposed based on physical insight, simplicity, and deterministic equivalent modeling to account for uncertainty. This kernel is based on a Stokes number method where uncertainty in the Stokes number is characterized by polynomial chaos expansions. The magnitude of the coalescence kernel is proportional to the probability of the distribution of Stokes number exceeding a critical value. This mechanistic/semiempirical approach to fluid‐bed agglomeration fosters an environment for process scaleup by eliminating specific equipment and process variable constraints to focus on the underlying mechanisms for proper scale‐up procedures. Model predictions using this new kernel are then compared to experimental pilot‐plant observations.

Dextranomer for treatment of venous leg ulcers: paste versus bead formulation

Twenty-nine patients with a total of 32 venous or mixed venous/arterial exudative leg ulcers were enrolled in this open-label, randomized, multicenter, parallel-group study—19 ulcers were treated with dextranomer paste and 13 ulcers were treated with dextranomer beads. Treatment was applied at least once daily and continued for a maximum of 21 days, or until the ulcer was clean and covered with new granulation tissue. The clinical efficacy of dextranomer paste was comparable to that of dextranomer beads, with improvement in the extent of granulation (by 72% and 77%, respectively) and reduction in the area of the lesion affected by pus and debris (by 84% and 77%, respectively). Local irritation was not evident with either dextranomer formulation. However, because the paste may be easier to apply than the bead formulation, the paste may be preferable for the treatment of such complicated wounds as leg ulcers.

Renin-1 is essential for normal renal juxtaglomerular cell granulation and macula densa morphology.

The secretion of renin from granules stored in renal juxtaglomerular cells plays a key role in blood pressure homeostasis. The synthesis and release of renin and the extent of granulation is regulated by several mechanisms including signaling from the macula densa, neuronal input, and blood pressure. Through the use of a gene-targeting vector containing homology arms generated using the polymerase chain reaction, we have inactivated the Ren-1(d) gene, one of two mouse genes encoding renin, and report that lack of renin-1(d) results in altered morphology of the macula densa of the kidney distal tubule and complete absence of juxtaglomerular cell granulation. Furthermore, Ren-1(d-/-) mice exhibit sexually dimorphic hypotension. The altered growth morphology of the macula densa in Ren-1(d)-null mice should provide a tool for the investigation of the JG cell-macula densa signaling. Furthermore, the current data indicate that expression of the Ren-1(d) gene is a prerequisite for the formation of storage granules, even though the related protein renin-2 is present in these mice, suggesting that renin-1(d) and renin-2 are secreted by distinct pathways in vivo.

A Point Mutation in the Catalytic Domain of c-kit Induces Growth Factor Independence, Tumorigenicity, and Differentiation of Mast Cells

The murine W and Steel loci encode the Kit receptor tyrosine kinase and its ligand, Steel factor, respectively. Loss of function mutations at either the W or Sl loci lead to a variety of pleiotropic developmental defects, including mast cell deficiency and severe macrocytic anemia. In addition to these loss-of-function mutations, gain-of-function mutations in c-kit, leading to constitutive activation of the Kit receptor, have also been identified in both rodent and human mastocytomas. In this study, we have examined the transforming potential and biologic effects of a point mutation that results in substitution of the aspartic acid at codon 814 in the cytoplasmic kinase domain to tyrosine (D814Y) by introducing either wild-type (Kit) or mutant KitD814Y (KDY) cDNA into an interleukin-3-dependent mast cell line IC2. Stimulation of cells expressing the wild-type Kit receptor (IC2/Kit) with Steel factor in vitro resulted in a short-term growth response, whereas IC2/KDY cells were capable of sustained proliferation in a ligand-independent manner. In addition, expression of KDY resulted in the oncogenic transformation of IC2 cells, as determined by colony formation in vitro in the absence of exogenous growth factors and the formation of mastocytomas in vivo in syngeneic DBA/2 mice. Surprisingly, KDY expression in IC2 cells triggered dramatic changes in cell size and the extent of granulation. In addition, KDY induced the expression of mouse mast cell protease-4 (MMCP-4) and MMCP-6. In contrast, neither of these molecular or cellular changes was observed in IC2/Kit cells treated with Steel factor. These results show that the D814Y mutation in the cytoplasmic kinase domain of the Kit receptor induces ligand-independent mast cell growth in vitro, tumorigenicity in vivo, and mast cell differentiation.

The effect of process parameters on drum granulation of fertilizers with broad size distributors

The effect of moisture content, particle size distribution and binder properties on the granulation of ammonium sulphate (AS), monoammonium phosphate (MAP) and diammonium phosphate (DAP) were investigated using experiments carried out in a 0.31 m diameter laboratory granulation drum. Broad initial size distributions were used to simulate recycle size distributions in operating granulation circuits. Granulation extent increases with the available solution phase for a given fertilizer salt. However, differences in granulation extent for different salts cannot be explained by their differences in solubility alone. Other properties of the solution phase binder, especially viscosity, are also important. At low moisture content and for low binder viscosity (MAP), an equilibrium size distribution is reached in less than 5 min. At higher moisture contents and binder viscosities (DAP), granulation continues up to at least 15 min before equilibrium size distribution is reached. The initial size distribution has a strong and complex effect on the granulation process. This extent of granulation goes through a maximum as the proportion of fine (minus 1 mm) in the initial size distribution increases. This effect is attributed to the changes in granule porosity and deformability. A two-stage granulation mechanism is proposed based on the analysis of granulation regimes given by Ennis . In the first stage (non-inertial regime), successful coalescence is independent of particle sizes. An equilibrium granule size distribution is quickly attained. In the second stage (inertial regime), at higher moisture contents, preferential coalescence predominates, leading to a significant growth of the large granules. The size distribution is subsequently widened. This mechanism is consistent with the experimental results. The analysis of granulation regimes given by Ennis successfully explains the effects of process parameters (liquid content, binder viscosity and initial size distribution) on the extent of granulation and the shape of the granule size distributions.

Effect of Urea in Sulfonamide Base on Healing of Clean Skin Wounds in Rabbits.

SummaryUrea retards the rate of epithelization of open skin wounds of rabbits, but stimulates the rate and extent of formation of granulation tissue; 40%, 10%, and 2% levels of urea in a glyceride jelly base containing sulfanilamide or sulfathiazole retard the average rate of epithelization 108%, 16%, and 20% respectively; 40% and 10%, levels of urea promote the rate and extent of granulation 36% and 19% respectively, and 2% urea has little or no effect.