Bulk Flow Optimisation of Amorphous Solid Dispersion Excipient Powders through Surface Modification.

Particulate amorphous solid dispersions (ASDs) have been recognised for their potential to enhance the performance of various solid dose forms, especially oral bioavailability and macromolecule stability. However, the inherent nature of spray-dried ASDs leads to their surface cohesion/adhesion, including hygroscopicity, which hinders their bulk flow and affects their utility and viability in terms of powder production, processing, and function. This study explores the effectiveness of L-leucine (L-leu) coprocessing in modifying the particle surface of ASD-forming materials. Various contrasting prototype coprocessed ASD excipients from both the food and pharmaceutical industries were examined for their effective coformulation with L-leu. The model/prototype materials included maltodextrin, polyvinylpyrrolidone (PVP K10 and K90), trehalose, gum arabic, and hydroxypropyl methylcellulose (HPMC E5LV and K100M). The spray-drying conditions were set such that the particle size difference was minimised, so that it did not play a substantial role in influencing powder cohesion. Scanning electron microscopy was used to evaluate the morphology of each formulation. A combination of previously reported morphological progression typical of L-leu surface modification and previously unreported physical characteristics was observed. The bulk characteristics of these powders were assessed using a powder rheometer to evaluate their flowability under confined and unconfined stresses, flow rate sensitivities, and compactability. The data showed a general improvement in maltodextrin, PVP K10, trehalose and gum arabic flowability measures as L-leu concentrations increased. In contrast, PVP K90 and HPMC formulations experienced unique challenges that provided insight into the mechanistic behaviour of L-leu. Therefore, this study recommends further investigations into the interplay between L-leu and the physico-chemical properties of coformulated excipients in future amorphous powder design. This also revealed the need to enhance bulk characterisation tools to unpack the multifactorial impact of L-leu surface modification.

Highlighting DEM's Potential to Gauge Mechanistic Attributes of MUPS Tablet and Capsule Formulations.

Simulation of pharmaceutical unit operations by the discrete element method (DEM) has elevated our understanding of the impact of single-particle interactions on themselves, and on the entire tablets/powder. Studies in the past have shown how this knowledge helps to mitigate/solve multiple challenges during conventional formulation and process development/modernization/troubleshooting, with minimal use of active drug material. This communication adds to this- highlighting the tool's potential for a rapid preliminary assessment of the mechanistic attributes of multiple unit particle system (MUPS) based tablet and capsule drug products.

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.

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.

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

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.

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.

Unified compaction curve model for tensile strength of tablets made by roller compaction and direct compression.

A model that describes the relationship between roller-compaction conditions and tablet strength is proposed. The model assumes that compaction is cumulative during roller compaction and subsequent granule compaction, and compact strength (ribbon and tablet) is generated irreversibly as if strength is controlled by plastic deformation of primary particles only. Roller-compaction is treated as a compaction step where the macroscopic ribbon strength is subsequently destroyed in milling. This loss in strength is irreversible and tablets compressed from the resulting granulation are weaker than those compressed by direct compression at the same compression force. Roller-compacted ribbons were produced at a range of roll forces for three formulations and subsequently milled and compacted into tablets. Once the total compaction history is taken in account, the compaction behavior of the uncompacted blends and the roller-compacted granules ultimately follow a single master compaction curve--a unified compaction curve (UCC). The model successfully described the compaction behavior of DC grade starch and formulations of lactose monohydrate with 50% or more microcrystalline cellulose, and may be more generally applicable to systems containing significant proportions of any plastically deforming material, including MCC and starch.

Drop penetration into porous powder beds.

The kinetics of drop penetration were studied by filming single drops of several different fluids (water, PEG200, PEG600, and HPC solutions) as they penetrated into loosely packed beds of glass ballotini, lactose, zinc oxide, and titanium dioxide powders. Measured times ranged from 0.45 to 126 s and depended on the powder particle size, viscosity, surface tensions, and contact angle. The experimental drop penetration times were compared to existing theoretical predictions by M. Denesuk et al. (J. Colloid Interface Sci.158, 114, 1993) and S. Middleman ("Modeling Axisymmetric Flows: Dynamics of Films, Jets, and Drops," Academic Press, San Diego, 1995) but did not agree. Loosely packed powder beds tend to have a heterogeneous bed structure containing large macrovoids which do not participate in liquid flow but are included implicitly in the existing approach to estimating powder pore size. A new two-phase model was proposed where the total volume of the macrovoids was assumed to be the difference between the bed porosity and the tap porosity. A new parameter, the effective porosity epsilon(eff), was defined as the tap porosity multiplied by the fraction of pores that terminate at a macrovoid and are effectively blocked pores. The improved drop penetration model was much more successful at estimating the drop penetration time on all powders and the predicted times were generally within an order of magnitude of the experimental results.