Ron J. Roberts

Practical application of roller compaction process modeling

Abstract Very limited work has been reported on comparing the performance of the roller compaction process at different scales. The majority of the approaches highlighted in the literature discuss the applicability of using confined uniaxial compaction for predicting the performance of the roller compaction process. In this paper a method was developed that allows the rolling theory of granular solids developed by Johanson [Johanson, J. R. (1965). A rolling theory for granular solids. ASME, Journal of Applied Mechanics Series E, 32(4), 842–848] to be used to infer the underlying material parameters from small-scale roller compaction experiments for both separation controlled or screw controlled configurations. Once these parameters are determined, the model can be used for predictive process design and scale-up in order to achieve target outputs such as ribbon density and throughput. The peak pressure, predicted by the model, can also be used to present roller compaction of a given formulation from a scale-independent perspective. This approach can be used to justify process parameter and equipment flexibility in the context of a pharmaceutical design space based on a proven acceptable range of peak pressures, or achieving target intermediate quality attributes, such as ribbon density.

A comparative study of roll compaction of free-flowing and cohesive pharmaceutical powders

Roll compaction is widely adopted as a dry granulation method in the pharmaceutical industry. The roll compaction behaviour of feed powders is primarily governed by two parameters: the maximum pressure and the nip angle. Although the maximum pressure can be measured directly using pressure sensors fitted in the rolls, it is not a trivial task to determine the nip angle, which is a measure of the size of the compaction zone and hence the degree of compression. Thus a robust approach based upon the calculation of the pressure gradient, which can be obtained directly from experiments using an instrumented roll compactor, was developed. It has been shown that the resulting nip angles are comparable to those obtained using the methods reported in literature. Nevertheless, the proposed approach has distinctive advantages including (1) it is based on the intrinsic features of slip and no-slip interactions between the powder and roll surface and (2) it is not necessary to carry out wall friction measurements that involve plates that may not be representative of the roll compactor in terms of the surface topography and surface energy. The method was evaluated by investigating the effect of roll speed for two pharmaceutical excipients with distinctive material properties: microcrystalline cellulose (MCC) and di-calcium phosphate dihydrate (DCPD). It was found that the maximum pressure and nip angle for DCPD, which is a cohesive powder, decrease sharply with increasing roll speed whereas they are essentially independent of roll speed for MCC, which is an easy flowing powder. The roll compaction behaviour of MCC-DCPD mixtures with various compositions was also investigated in order to evaluate the effect of flowability. It was found that the nip angle and maximum pressure generally increased with improved flowability of the feed powders.

An experimental investigation of temperature rise during compaction of pharmaceutical powders

During pharmaceutical powder compaction, temperature rise in the compressed powder can affect physiochemical properties of the powder, such as thermal degradation and change in crystallinity. Thus, it is of practical importance to understand the effect of process conditions and material properties on the thermal response of pharmaceutical formulations during compaction. The aim of this study was to examine the temperature rise of pharmaceutical powders during tableting, in particular, to explore how the temperature rise depends on material properties, compression speed and tablet shape. Three grades of microcrystalline cellulose (MCC) were considered: MCC Avicel pH 101, MCC Avicel pH 102 and MCC DG. These powders were compressed using a compaction simulator at various compaction speeds (10-500mm/s). Flat faced, shallow convex and normal convex tablets were produced and temperature distributions on the surface of theses tablets upon ejection were examined using an infrared thermoviewer. It was found that an increase in the compaction speed led to an increase in the average surface temperature. A higher surface temperature was induced when the powder was compressed into a tablet with larger surface curvature. This was primarily due to the increasing degree of powder deformation (i.e. the volume reduction) and the effect of interparticule/wall friction.

A combined modelling and experimental study of the surface energetics of α-lactose monohydrate

The surface energy of alpha-lactose monohydrate measured by inverse gas chromatography (IGC) is reported along with a dynamic molecular modelling study of the interaction of the various molecular probes with different surfaces of alpha-lactose monohydrate. The IGC results show that alpha-lactose monohydrate is acidic in nature. Using quantitative calculations of the energy of adsorption, the acidic nature of the surface is confirmed and the calculated values agree closely with the experimentally measured values. Along with the acidic nature, dynamic molecular modelling also reveals that the presence of a channel and water molecules on a surface affects the surface energetics of that face. The presence of water on the surface can decrease or increase the surface energy by either blocking or attracting a probe molecule, respectively. This property of water depends on its position and association with other functional groups present on the surface. The effect of a channel or cavity on the surface energy is shown to depend on its size, which determines whether the functional groups in the channel are assessable by probe molecules or not. Overall molecular modelling explains, at the molecular level, the effect of different factors affecting the surface energy of individual faces of the crystal.

A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures

A new model to predict the compressibility and compactability of mixtures of pharmaceutical powders has been developed. The key aspect of the model is consideration of the volumetric occupancy of each powder under an applied compaction pressure and the respective contribution it then makes to the mixture properties. The compressibility and compactability of three pharmaceutical powders: microcrystalline cellulose, mannitol and anhydrous dicalcium phosphate have been characterised. Binary and ternary mixtures of these excipients have been tested and used to demonstrate the predictive capability of the model. Furthermore, the model is shown to be uniquely able to capture a broad range of mixture behaviours, including neutral, negative and positive deviations, illustrating its utility for formulation design.

N-(3-Methoxy-5-methyl­pyrazin-2-yl)-2-[4-(1,3,4-oxa­diazol-2-yl)­phenyl]­pyridine-3-sulfon­amide (ZD4054 Form 1)

The title compound, C19H16N6O4S, crystallizes from N-methylxadpyridine in the centrosymmetric space group P21/n with four molxadecules in the unit cell. The molxadecule has 11 heteroatoms, of which only one is protonated. This potential hydrogen-bond donor, viz. the NH amide group, participates in both intra- and intermolecular hydrogen-bond interactions, thus contributing to the stabilization of the molecular conformation and the linking of molxadecules as dimers. The hairpin-like folded molxadecule is arranged with three of its four aromatic rings in two parallel planes intersected by a sulfonxadamide moiety. In this way, the molxadecules stack efficiently, facilitated by short-range van der Waals forces. No residual volume for solvent inclusion was found.

Experimental Investigation of Milling of Roll Compacted Ribbons

In pharmaceutical industries, roll compaction is a preferred dry granulation process for moisture and heat sensitive formulations. The roll compacted ribbons are milled to granules for subsequent tablet manufacturing. Thus, milling is also one of the critical processes that determines the properties of the granules and hence the tablets. However, the milling behaviour of pharmaceutical ribbons is not well understood. In the current work, milling experiments with ribbons made from a common pharmaceutical excipient, microcrystal cellulose (MCC), were carried out using an oscillating mill with a modified sealing system. A first order kinetics expression was proposed to describe the mass throughput of the process. It was found that the solid fraction of the feed ribbons and the operating milling speed significantly affect the mass throughput and mean granule size. In addition, two regimes dominated by the milling speed were observed, in which distinctive milling mechanisms of abrasion and impact were involved.