Dimensionless Spray Flux Research Articles

Impacts of the size distributions and protein contents of the native wheat powders in their structuration behaviour by wet agglomeration

The control of the wet agglomeration processes of powders depends on the contribution of the characteristics of the native powders. The objective of this work is to specifically investigate the contribution of the size distribution (d50 and span) and composition (the protein contents) of the native particles, on the dimensional and structural characteristics of the wet agglomerates. Different fractions of native semolina with contrasted size properties (d50 and span) and protein content are used as raw materials. The wet granulation is conducted using a low shear granulator and liquid spraying condition at constant dimensionless spray flux. The structure properties are evaluated by the distribution of the measured values of the size, water content and compactness. We observed specific effects of the span and the median diameter of native powders on the size distributions of the wet agglomerates. Using small native particles (d50 < 250 μm) improves the homogeneity of the size distributions. Using slightly dispersed native particles (span < 1.0) leads to a better uniformity on the size distributions. Using semolina with high protein content could lead to a narrow size distribution by limiting the process of fragmentation and the formation of fragments in the bed. We showed that the mechanisms involved in the agglomeration process are similar whatever the size distribution and the protein content of the native powders.

Development and evaluation of a dimensionless mechanistic pan coating model for the prediction of coated tablet appearance

A mathematical, mechanistic tablet film-coating model has been developed for pharmaceutical pan coating systems based on the mechanisms of atomisation, tablet bed movement and droplet drying with the main purpose of predicting tablet appearance quality. Two dimensionless quantities were used to characterise the product properties and operating parameters: the dimensionless Spray Flux (relating to area coverage of the spray droplets) and the Niblett Number (relating to the time available for drying of coating droplets). The Niblett Number is the ratio between the time a droplet needs to dry under given thermodynamic conditions and the time available for the droplet while on the surface of the tablet bed. The time available for drying on the tablet bed surface is critical for appearance quality. These two dimensionless quantities were used to select process parameters for a set of 22 coating experiments, performed over a wide range of multivariate process parameters. The dimensionless Regime Map created can be used to visualise the effect of interacting process parameters on overall tablet appearance quality and defects such as picking and logo bridging.

Scale-up of a high shear wet granulation process using a nucleation regime map approach

Scale-up of the high shear wet granulation (HSWG) process is considered a challenge because HSWG is complex and influenced by numerous factors, including equipment, formulation, and process variables. For a system of microcrystalline cellulose and water, HSWG experiments at three scales (1, 2, and 4L working vessel) were conducted with a granulator. Scale-up was implemented on the basis of a nucleation regime map approach. To keep dimensionless spray flux and drop penetration time constant, water addition time at three processing scales were 300, 442, and 700s, respectively. The other process parameters were kept unchanged. Granule size distributions were plotted and compared, and scanning electron microscopy was used to analyze granule surface morphology. Physical characterization was undertaken using a modified SeDeM method. At nearly all scales, granule yield was greater than 85% and all the cosine values were larger than 0.89. At the same experiment points, granules at all scales had similar surface morphology and similar physical characteristics. The results demonstrate that a rational scaling-up of the HSWG process is feasible using a regime map approach.

A priori performance prediction in pharmaceutical wet granulation: Testing the applicability of the nucleation regime map to a formulation with a broad size distribution and dry binder addition

In this study, Hapgood's nucleation regime map ( Hapgood et al., 2003) was tested for a formulation that consists of an active pharmaceutical ingredient (API) of broad size distribution and a fine dry binder. Gabapentin was used as the API and hydroxypropyl cellulose (HPC) as the dry binder with deionized water as the liquid binder. The formulation was granulated in a 6 l Diosna high shear granulator. The effect of liquid addition method (spray, dripping), liquid addition rate (29–245 g/min), total liquid content (2, 4 and 10%), and impeller speed (250 and 500 rpm) on the granule size distribution and lump formation were investigated. Standard methods were successfully used to characterize the process parameters (spray drop size, spray geometry and powder surface velocity) for calculating the dimensionless spray flux. However, the addition of dry binder had a very strong effect on drop penetration time that could not be predicted from simple capillary flow considerations. This is most likely due to preferential liquid penetration into the fine pores related to the dry binder particles and subsequent partial softening and dissolution of the binder. For systems containing a dry binder or other amorphous powders, it is recommended that drop penetration time be measured directly for the blended formulation and then scaled to the drop size during spraying. Using these approaches to characterize the key dimensionless groups (dimensionless spray flux and drop penetration time), Hapgood's nucleation regime map was successfully used to predict a priori the effect of process conditions on the quality of the granule size distribution as measured by lump formation and the span of the size distribution, both before and after wet massing for range of conditions studied. Wider granule size distributions and higher amount of lumps were obtained moving from intermediate to mechanical dispersion regime. Addition of the liquid in the dripping mode gave the broadest size distribution with ungranulated fines and highest percentage of lumps compared to spraying mode. Addition of the liquid by spraying in the intermediate regime gave the narrowest size distribution with the lowest amount of lumps. The effects of impeller speed and wet massing time on granule size distribution were complex. At 2% liquid content, increasing the impeller speed and adding wet massing time caused some breakage of lumps and the production of fines. At higher liquid contents, the effects were less clear, likely due to a balance between increased breakage and increased granule consolidation and growth. Nevertheless, this work has demonstrated that for complex formulations with dry binder addition, the final granule size distribution still depends strongly on the homogeneity of the initial liquid distribution which is well predicted by the nucleation regime map analysis.

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.

Drop penetration time in heterogeneous powder beds

Abstract 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.

A method to predict nuclei size distributions for use in models of wet granulation

Models of granulation and agglomeration are becoming more sophisticated and accurate, but nucleation is poorly understood. Models of granulation processes typically either use simplistic nucleation assumptions; complex multi-phase simulations or deliberately focus on the final granulation stages only. Here, we validate a simple method to generate nuclei size distributions using the dimensionless spray flux parameter, for future use in granulation models in the drop controlled regime. Dimensionless spray flux describes the spray density in the spray zone, which is closely related to the Poisson distribution. A simple model to estimate the nuclei size distribution at a range of spray flux conditions was compared with data generated in a previous study. The simulations were in reasonable agreement with experimental data at low penetration time and low spray flux ( Ψ a < 0.3) but diverged when either the spray flux was >0.5. For a longer penetration time system, the simulations and experimental results agreed up to Ψ a = 0.5. Multi-modal experimental results could not be modeled. Spray flux derived models of nuclei size distributions are useful nucleation granulation models, provided that the simulations are restricted to the drop controlled regime ( Ψ a < 0.1) and extended to higher spray fluxes with caution.

Modelling nucleation in wet granulation

Nucleation is the first stage in any granulation process where binder liquid first comes into contact with the powder. This paper investigates the nucleation process where binder liquid is added to a fine powder with a spray nozzle. The dimensionless spray flux approach of Hapgood et al. (Powder Technol. 141 (2004) 20) is extended to account for nonuniform spray patterns and allow for overlap of nuclei granules rather than spray drops. A dimensionless nuclei distribution function which describes the effects of the design and operating parameters of the nucleation process (binder spray characteristics, the nucleation area ratio between droplets and nuclei and the powder bed velocity) on the fractional surface area coverage of nuclei on a moving powder bed is developed. From this starting point, a Monte Carlo nucleation model that simulates full nuclei size distributions as a function of the design and operating parameters that were implemented in the dimensionless nuclei distribution function is developed. The nucleation model was then used to investigate the effects of the design and operating parameters on the formed nuclei size distributions and to correlate these effects to changes of the dimensionless nuclei distribution function. Model simulations also showed that it is possible to predict nuclei size distributions beyond the drop controlled nucleation regime in Hapgood's nucleation regime map. Qualitative comparison of model simulations and experimental nucleation data showed similar shapes of the nuclei size distributions. In its current form, the nucleation model can replace the nucleation term in one-dimensional population balance models describing wet granulation processes. Implementation of more sophisticated nucleation kinetics can make the model applicable to multi-dimensional population balance models.

Dimensionless spray flux in wet granulation: Monte-Carlo simulations and experimental validation

Dimensionless spray flux Ψ a is a dimensionless group that characterises the three most important variables in liquid dispersion: flowrate, drop size and powder flux through the spray zone. In this paper, the Poisson distribution was used to generate analytical solutions for the proportion of nuclei formed from single drops ( f single) and the fraction of the powder surface covered by drops ( f covered) as a function of Ψ a. Monte-Carlo simulations were performed to simulate the spray zone and investigate how Ψ a, f single and f covered are related. The Monte-Carlo data was an excellent match with analytical solutions of f covered and f single as a function of Ψ a. At low Ψ a, the proportion of the surface covered by drops ( f covered) was equal to Ψ a. As Ψ a increases, drop overlap becomes more dominant and the powder surface coverage levels off. The proportion of nuclei formed from single drops ( f single) falls exponentially with increasing Ψ a. In the ranges covered, these results were independent of drop size, number of drops, drop size distribution (mono-sized, bimodal and trimodal distributions), and the uniformity of the spray. Experimental data of nuclei size distributions as a function of spray flux were fitted to the analytical solution for f single by defining a cutsize for single drop nuclei. The fitted cutsizes followed the spray drop sizes suggesting that the method is robust and that the cutsize does indicate the transition size between single drop and agglomerate nuclei. This demonstrates that the nuclei distribution is determined by the dimensionless spray flux and the fraction of drop controlled nuclei can be calculated analytically in advance.

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.

Nucleation regime map for liquid bound granules

AbstractNucleation is the first step in granulation where the powder and liquid first contact. Two types of nucleation in wet granulation processes are proposed. Drop controlled nucleation, where one drop forms one nucleus, occurs when drops hitting the powder surface do not overlap (low spray flux Ψa) and the drop must wet quickly into the bed (short drop penetration time tp). If either criterion is not met, powder mixing characteristics will dominate (mechanical dispersion regime). Granulation experiments were performed with lactose powder, water, PEG200, and 7% HPC solution in a 6 L and a 25 L mixer granulator. Size distributions were measured as the drop penetration time and spray flux were varied. At short penetration times, decreasing Ψa caused the nuclei distribution to become narrower. When drop penetration time was high, the nuclei size distribution was broad independent of changes in dimensionless spray flux. Nucleation regime maps were plotted for each set of experiments in each mixer as a function of the dimensionless distribution width δ. The nucleation regime map demonstrates the interaction between drop penetration time and spray flux in nucleation. The narrowest distribution consistently occurred at low spray flux and low penetration time, proving the existence of the drop controlled regime. The nucleation regime map provides a rational basis for design and scale‐up of nucleation and wetting in wet granulation.

Liquid distribution in wet granulation: dimensionless spray flux

This study investigates binder distribution in wet granulation and focuses on the nucleation zone, which is the area where the liquid binder and powder surface come into contact and form the initial nuclei. An equipment independent parameter, dimensionless spray flux Ψa, is defined to characterise the most important process parameters in the nucleation process: solution flowrate, powder flux, and binder drop size. Ex-granulator experiments are used to study the relationship between dimensionless spray flux, process variables and the coverage of binder fluid on the powder surface. Lactose monohydrate powder on a variable speed riffler passed under a flat spray once only. Water and 7% HPC solution at two spray pressures were used as binders. Experiments with red dye and image analysis demonstrate that changes in dimensionless spray flux correlate with a measurable difference in powder surface coverage. Nucleation experiments show that spray flux controls the size and shape of the nuclei size distribution. At low Ψa, the system operates in the drop controlled regime, where one drop forms one nucleus and the nuclei size distribution is narrow. At higher Ψa, the powder surface cakes creating a broader size distribution. For controlled nucleation with the narrowest possible size distribution, it is recommended that the dimensionless spray flux be less than 0.1 to be in the drop-controlled regime.