Karen Hapgood

Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review

Wet agglomeration processes have traditionally been considered an empirical art, with great difficulties in predicting and explaining observed behaviour. Industry has faced a range of problems including large recycle ratios, poor product quality control, surging and even the total failure of scale up from laboratory to full scale production. However, in recent years there has been a rapid advancement in our understanding of the fundamental processes that control granulation behaviour and product properties. This review critically evaluates the current understanding of the three key areas of wet granulation processes: wetting and nucleation, consolidation and growth, and breakage and attrition. Particular emphasis is placed on the fact that there now exist theoretical models which predict or explain the majority of experimentally observed behaviour. Provided that the correct material properties and operating parameters are known, it is now possible to make useful predictions about how a material will granulate. The challenge that now faces us is to transfer these theoretical developments into industrial practice. Standard, reliable methods need to be developed to measure the formulation properties that control granulation behaviour, such as contact angle and dynamic yield strength. There also needs to be a better understanding of the flow patterns, mixing behaviour and impact velocities in different types of granulation equipment

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 Psi (a), 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 Psi (a), the system operates in the drop controlled regime, where one drop forms one nucleus and the nuclei size distribution is narrow. At higher Psi (a), 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

Scale-up of mixer granulators for effective liquid distribution

There is considerable anecdotal evidence from industry that poor wetting and liquid distribution can lead to broad granule size distributions in mixer granulators. Current scale-up scenarios lead to poor liquid distribution and a wider product size distribution. There are two issues to consider when scaling up: the size and nature of the spray zone and the powder flow patterns as a function of granulator scale. Short, nucleation-only experiments in a 25L PMA Fielder mixer using lactose powder with water and HPC solutions demonstrated the existence of different nucleation regimes depending on the spray flux Ψa—from drop-controlled nucleation to caking. In the drop-controlled regime at low Ψa values, each drop forms a single nucleus and the nuclei distribution is controlled by the spray droplet size distribution. As Ψa increases, the distribution broadens rapidly as the droplets overlap and coalesce in the spray zone. The results are in excellent agreement with previous experiments and confirm that for drop-controlled nucleation, Ψa should be less than 0.1. Granulator flow studies showed that there are two powder flow regimes—bumping and roping. The powder flow goes through a transition from bumping to roping as impeller speed is increased. The roping regime gives good bed turn over and stable flow patterns. This regime is recommended for good liquid distribution and nucleation. Powder surface velocities as a function of impeller speed were measured using high-speed video equipment and MetaMorph image analysis software. Powder surface velocities were 0.2 to 1 ms−1—an order of magnitude lower than the impeller tip speed. Assuming geometrically similar granulators, impeller speed should be set to maintain constant Froude number during scale-up rather than constant tip speed to ensure operation in the roping regime.

Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate

Abstract Intensive dry powder coating (mechanofusion) with tablet lubricants has previously been shown to give substantial powder flow improvement. This study explores whether the mechanofusion of magnesium stearate (MgSt), on a fine drug powder can substantially improve flow, without preventing the powder from being directly compacted into tablets. A fine ibuprofen powder, which is both cohesive and possesses a low-melting point, was dry coated via mechanofusion with between 0.1% and 5% (w/w) MgSt. Traditional low-shear blending was also employed as a comparison. No significant difference in particle size or shape was measured following mechanofusion. For the low-shear blended powders, only marginal improvement in flowability was obtained. However, after mechanofusion, substantial improvements in the flow properties were demonstrated. Both XPS and ToF-SIMS demonstrated high degrees of a nano-scale coating coverage of MgSt on the particle surfaces from optimized mechanofusion. The study showed that robust tablets were produced from the selected mechanofused powders, at high-dose concentration and tablet tensile strength was further optimized via addition of a Polyvinylpyrrolidone (PVP) binder (10% w/w). The tablets with the mechanofused powder (with or without PVP) also exhibited significantly lower ejection stress than those made of the raw powder, demonstrating good lubrication. Surprisingly, the release rate of drug from the tablets made with the mechanofused powder was not retarded. This is the first study to demonstrate such a single-step dry coating of model drug with MgSt, with promising flow improvement, flow-aid and lubrication effects, tabletability and also non-inhibited dissolution rate.

Chapter 20 Granulation rate processes

Publisher Summary Wet granulation is a complex process with several competing physical phenomena occurring in the granulator, which ultimately leads to the formation of the granules. These phenomena are divided into three groups of rate processes: (1) wetting, nucleation, and binder distribution, (2) consolidation and growth, and (3) attrition and breakage. The physical phenomena that control these processes are the same, independent of the type of granulation used. Granule size, size distribution, and porosity, as well as many other key product attributes are controlled by the balance of the rate processes that occur in the granulator. This chapter examines the underlying physics behind each rate process, defines the controlling formulation properties and process parameters for each rate process, uses regime maps to establish the operating regime for the granulator; and provides quantitative relationships to predict the effect of changing operating parameters and formulation properties. This chapter focuses on developments in the past decade where substantial advances in quantitative understanding of granulation rate processes have been made with an emphasis on work done by our group at The University of Queensland and The University of Newcastle. The philosophy of this chapter is to characterize process parameters in generic terms that are equipment independent (collision velocity, powder surface flux, etc.).

Influence of coating material on the flowability and dissolution of dry-coated fine ibuprofen powders

This study investigates the effects of a variety of coating materials on the flowability and dissolution of dry-coated cohesive ibuprofen powders, with the ultimate aim to use these in oral dosage forms. A mechanofusion approach was employed to apply a 1% (w/w) dry coating onto ibuprofen powder with coating materials including magnesium stearate (MgSt), L-leucine, sodium stearyl fumarate (SSF) and silica-R972. No significant difference in particle size or shape was measured following mechanofusion with any material. Powder flow behaviours characterised by the Freeman FT4 system indicated coatings of MgSt, L-leucine and silica-R972 produced a notable surface modification and substantially improved flow compared to the unprocessed and SSF-mechanofused powders. ToF-SIMS provided a qualitative measure of coating extent, and indicated a near-complete layer on the drug particle surface after dry coating with MgSt or silica-R972. Of particular note, the dissolution rates of all mechanofused powders were enhanced even with a coating of a highly hydrophobic material such as magnesium stearate. This surprising increase in dissolution rate of the mechanofused powders was attributed to the lower cohesion and the reduced agglomeration after mechanical coating.

Drug distribution in wet granulation: foam versus spray

Foam granulation technology is a new wet granulation approach for pharmaceutical formulations. This study evaluates the performance of foam and spray granulation in achieving uniform drug distribution using a model formulation. To observe wetting and nuclei formation, single drop/foam penetration experiments were performed on a static powder bed comprised of varying compositions of hydrophilic/hydrophobic glass ballotini, and hydrophilic lactose/hydrophobic salicylic acid respectively. High shear granulation experiments were performed in a 5L mixer using varying compositions of hydrophilic lactose and hydrophobic salicylic acid. Four percent hydroxylpropyl methylcellulose (HPMC) solution was delivered at 90 g/min as either a foam (92% FQ) or an atomized spray whilst recording impeller power consumption. After drying, the granule size distribution was measured and the granule composition was estimated using gravimetric filtration in methanol. Foam penetration was less dependent on the powder hydrophobicity compared to drop penetration. For glass ballotini powder mixtures, foam induced nucleation created nuclei with relatively uniform structure and size regardless of the powder hydrophobicity. For salicylic acid and lactose mixtures, increasing the proportion of salicylic acid reduced the nuclei granule size for both foam and drop binder addition. The granule drug distribution was not significantly affected by the binder addition method. Processing conditions, including liquid binder amount, impeller speed, wet massing, and the wettability properties of the formulation were the dominant factors for delivering homogeneous granules. The study reveals that foam and spray granulation involve different nucleation mechanisms – spray tends to incur early liquid penetration whereas foam granulation operates well in mechanical dispersion.

Single-step Coprocessing of Cohesive Powder via Mechanical Dry Coating for Direct Tablet Compression

This study aims at testing the feasibility of a single-step coating process to produce a powder formulation of active and inactive ingredients for direct compression. A cohesive ibuprofen powder was coprocessed with a coating material, a binder (polyvinylpyrrolidone K25), and a superdisintegrant (crospovidone). Magnesium stearate (MgSt), l-leucine, and silica were selected as coating materials (1% w/w). A coprocessed powder without any coating material was employed as a control. Coating with MgSt, l-leucine, or silica produced significantly improved powder flow in comparison to the control batch. Robust tablets were produced from the processed powders for each coating material. The tablets compacted using the coated powders with MgSt or l-leucine also exhibited significantly lower tablet ejection forces than the control batch, demonstrating their lubrication effect. Furthermore, the disintegration time and dissolution rates of these tablets made of the formulations coprocessed with lubricants were enhanced, even for those coated with the hydrophobic material such as MgSt that has been previously reported to inhibit dissolution. However, the tablets made with silica-coated powders would not disintegrate. This study indicated the feasibility of a single-step dry coating process to produce powders with both flow-aid and lubrication effects, which are suitable for direct compression.

The Environmental footprint of morphine: a life cycle assessment from opium poppy farming to the packaged drug

Objective To examine the environmental life cycle from poppy farming through to production of 100 mg in 100 mL of intravenous morphine (standard infusion bag). Design ‘Cradle-to-grave’ process-based life cycle assessment (observational). Settings Australian opium poppy farms, and facilities for pelletising, manufacturing morphine, and sterilising and packaging bags of morphine. Main outcome measures The environmental effects (eg, CO2 equivalent (‘CO2 e’) emissions and water use) of producing 100 mg of morphine. All aspects of morphine production from poppy farming, pelletising, bulk morphine manufacture through to final formulation. Industry-sourced and inventory-sourced databases were used for most inputs. Results Morphine sulfate (100 mg in 100 mL) had a climate change effect of 204 g CO2 e (95% CI 189 to 280 g CO2 e), approximating the CO2 e emissions of driving an average car 1 km. Water use was 7.8 L (95% CI 6.7– to 9.0 L), primarily stemming from farming (6.7 L). All other environmental effects were minor and several orders of magnitude less than CO2 e emissions and water use. Almost 90% of CO2 e emissions occurred during the final stages of 100 mg of morphine manufacture. Morphines packaging contributed 95 g CO2 e, which accounted for 46% of the total CO2 e (95% CI 82 to 155 g CO2 e). Mixing, filling and sterilisation of 100 mg morphine bags added a further 86 g CO2 e, which accounted for 42% (95% CI 80 to 92 g CO2 e). Poppy farming (6 g CO2 e, 3%), pelletising and manufacturing (18 g CO2 e, 9%) made smaller contributions to CO2 emissions. Conclusions The environmental effects of growing opium poppies and manufacturing bulk morphine were small. The final stages of morphine production, particularly sterilisation and packaging, contributed to almost 90% of morphines carbon footprint. Focused measures to improve the energy efficiency and sources for drug sterilisation and packaging could be explored as these are relevant to all drugs. Comparisons of the environmental effects of the production of other drugs and between oral and intravenous preparations are required.

A field study of lignite as a drying aid in the superheated steam drying of anaerobically digested sludge

Dried sludge is preferred when the sludge is either to be incinerated or used as a soil amendment. This paper focuses on superheated steam drying which has many benefits, because the system is totally enclosed, thereby minimising odours and particulate emissions. This work reports on field trials at a wastewater treatment plant where anaerobically digested sludge is dried immediately after being dewatered by belt press. The trials showed that unlike previous off-site tests, the sludge could be dried without the addition of a filter aid at a low production rate. However, the trials also confirmed that the addition of the lignite (brown coal) into the anaerobically digested sludge led to a more productive drying process, improved product quality and a greater fraction of the product being in the desired product size range. It is concluded that these results were achieved because the lignite helped to control the granule size in the dryer. Furthermore neither Salmonella spp or E coli were detected in the dried samples. Tests on spontaneous combustion show that this risk is increased in proportion to the amount of lignite used as a drying aid.