Influence of particle properties on powder bulk behaviour and processability.

Understanding interparticle interactions in powder systems is crucial to pharmaceutical powder processing. Nevertheless, there remains a great challenge in identifying the key factors affecting interparticle interactions. Factors affecting interparticle interactions can be classified in three different broad categories: powder properties, environmental conditions, and powder processing methods and parameters. Although, each of these three categories listed is known to affect interparticle interactions, the challenge remains in developing a mechanistic understanding on how combination of these three categories affect interparticle interactions. This review focuses on the recent advances on understanding the effect of powder properties, particularly particle properties, its effect on interparticle interactions and ultimately on powder bulk behaviour. Furthermore, this review also highlights how particle properties are affected by the particle processing route and parameters. Recent advances in developing a particle processing route to prepare particles with desired properties allowing desired interparticle interaction to deliver favoured powder bulk behaviour are also discussed. Perspectives for the development of potential particle processing approaches to control interparticle interaction are presented.

The Effect of Polymorphism on Surface Energetics of D-Mannitol Polymorphs.

The aim of this work was to assess the effect of different crystalline polymorphism on surface energetics of D-mannitol using finite dilution inverse gas chromatography (FD-IGC). Pure α, ß and δ polymorphs were prepared via solution crystallisation and characterised by powder X-ray diffraction (P-XRD). The dispersive surface energies were found to range from 43 to 34 mJ/m2, 50 to 41 mJ/m2, and 48 to 38 mJ/m2, for α, ß, and δ, respectively, for surface coverage ranging from 0.006 to 0.095. A deconvolution modelling approach was employed to establish their energy sites. The primary sites corresponded to maxima in the dispersive surface energy of 37.1 and 33.5; 43.3 and 39.5; and 38.6, 38.4 and 33.0; for α, ß, and δ, respectively. This methodology was also extended to an α-ß polymorph mixture to estimate the amount of the constituent α and ß components present in the sample. The dispersive surface energies of the α-ß mixture were found to be in the range of 48 to 37 mJ/m2 with 40.0, 42.4, 38.4 and 33.1 mJ/m2 sites. The deconvolution modelling method extracted the energy contribution of each of the polymorphs from data for the polymorphic mixture. The mixture was found to have a ß-polymorph surface content of ∼19%. This work shows the influence of polymorphism on surface energetics and demonstrates that FD-IGC coupled with a simple modelling approach to be a powerful tool for assessing the specific nature of this energetic distribution including the quantification of polymorphic content on the surface.

Measuring the sticking of mefenamic acid powders on stainless steel surface.

This study proposes an approach for quantifying the amount of pharmaceutical powder adhering (quality attribute) to the metals surfaces. The effect of surface roughness (detrimental attribute) on the amount of powder sticking to a stainless steel surface for a model pharmaceutical material is also qualitatively determined. Methodology to quantify powder adhesion to surfaces utilises a texture analyser and HPLC. The approach was validated to qualitatively investigate effect of metal surface roughness on adhesion of mefenamic acid. An increase in metal surface roughness resulted in an increase in cohesion. By increasing the average roughness from 289nm to 407nm, a 2.5 fold increase in amount adhering to metal was observed, highlighting the role of surface roughness on adhesion. The simplicity in experimental design with no requirement of specialised equipment and operational ease makes the approach very easy to adopt. Further, ease in interpreting results makes this methodology very attractive.

Effect of milling temperatures on surface area, surface energy and cohesion of pharmaceutical powders.

Particle bulk and surface properties are influenced by the powder processing routes. This study demonstrates the effect of milling temperatures on the particle surface properties, particularly surface energy and surface area, and ultimately on powder cohesion. An active pharmaceutical ingredient (API) of industrial relevance (brivanib alaninate, BA) was used to demonstrate the effect of two different, but most commonly used milling temperatures (cryogenic vs. ambient). The surface energy of powders milled at both cryogenic and room temperatures increased with increasing milling cycles. The increase in surface energy could be related to the generation of surface amorphous regions. Cohesion for both cryogenic and room temperature milled powders was measured and found to increase with increasing milling cycles. For cryogenic milling, BA had a surface area ∼ 5× higher than the one obtained at room temperature. This was due to the brittle nature of this compound at cryogenic temperature. By decoupling average contributions of surface area and surface energy on cohesion by salinization post-milling, the average contribution of surface energy on cohesion for powders milled at room temperature was 83% and 55% at cryogenic temperature.

Decoupling the contribution of surface energy and surface area on the cohesion of pharmaceutical powders.

PURPOSE: Surface area and surface energy of pharmaceutical powders are affected by milling and may influence formulation, performance and handling. This study aims to decouple the contribution of surface area and surface energy, and to quantify each of these factors, on cohesion. METHODS: Mefenamic acid was processed by cryogenic milling. Surface energy heterogeneity was determined using a Surface Energy Analyser (SEA) and cohesion measured using a uniaxial compression test. To decouple the surface area and surface energy contributions, milled mefenamic acid was "normalised" by silanisation with methyl groups, confirmed using X-ray Photoelectron Spectroscopy. RESULTS: Both dispersive and acid-base surface energies were found to increase with increasing milling time. Cohesion was also found to increase with increasing milling time. Silanised mefenamic acid possessed a homogenous surface with a surface energy of 33.1 ± 1.4 mJ/m(2) , for all milled samples. The cohesion for silanised mefenamic acid was greatly reduced, and the difference in the cohesion can be attributed solely to the increase in surface area. For mefenamic acid, the contribution from surface energy and surface area on cohesion was quantified to be 57% and 43%, respectively. CONCLUSIONS: Here, we report an approach for decoupling and quantifying the contribution from surface area and surface energy on powder cohesion.

Decoupling the contribution of dispersive and acid-base components of surface energy on the cohesion of pharmaceutical powders.

This study reports an experimental approach to determine the contribution from two different components of surface energy on cohesion. A method to tailor the surface chemistry of mefenamic acid via silanization is established and the role of surface energy on cohesion is investigated. Silanization was used as a method to functionalize mefenamic acid surfaces with four different functional end groups resulting in an ascending order of the dispersive component of surface energy. Furthermore, four haloalkane functional end groups were grafted on to the surface of mefenamic acid, resulting in varying levels of acid-base component of surface energy, while maintaining constant dispersive component of surface energy. A proportional increase in cohesion was observed with increases in both dispersive as well as acid-base components of surface energy. Contributions from dispersive and acid-base surface energy on cohesion were determined using an iterative approach. Due to the contribution from acid-base surface energy, cohesion was found to increase ∼11.7× compared to the contribution from dispersive surface energy. Here, we provide an approach to deconvolute the contribution from two different components of surface energy on cohesion, which has the potential of predicting powder flow behavior and ultimately controlling powder cohesion.

Effect of crystal habits on the surface energy and cohesion of crystalline powders.

The role of surface properties, influenced by particle processing, in particle-particle interactions (powder cohesion) is investigated in this study. Wetting behaviour of mefenamic acid was found to be anisotropic by sessile drop contact angle measurements on macroscopic (>1cm) single crystals, with variations in contact angle of water from 56.3° to 92.0°. This is attributed to variations in surface chemical functionality at specific facets, and confirmed using X-ray photoelectron spectroscopy (XPS). Using a finite dilution inverse gas chromatography (FD-IGC) approach, the surface energy heterogeneity of powders was determined. The surface energy profile of different mefenamic acid crystal habits was directly related to the relative exposure of different crystal facets. Cohesion, determined by a uniaxial compression test, was also found to relate to surface energy of the powders. By employing a surface modification (silanisation) approach, the contribution from crystal shape from surface area and surface energy was decoupled. By "normalising" contribution from surface energy and surface area, needle shaped crystals were found to be ∼2.5× more cohesive compared to elongated plates or hexagonal cuboid shapes crystals.