3D Characterisation of Dry Powder Inhaler Formulations: Developing X-ray Micro Computed Tomography Approaches.

Carrier-based dry powder inhaler (DPI) formulations need to be accurately characterised for their particle size distributions, surface roughnesses, fines contents and flow properties. Understanding the micro-structure of the powder formulation is crucial, yet current characterisation methods give incomplete information. Commonly used techniques like laser diffraction (LD) and optical microscopy (OM) are limited due to the assumption of sphericity and can give variable results depending on particle orientation and dispersion. The aim of this work was to develop new powder analytical techniques using X-ray computed tomography (XCT) that could be employed for non-destructive metrology of inhaled formulations. α-lactose monohydrate powders with different characteristics have been analysed, and their size and shape (sphericity/aspect ratio) distributions compared with results from LD and OM. The three techniques were shown to produce comparable size distributions, while the different shape distributions from XCT and OM highlight the difference between 2D and 3D imaging. The effect of micro-structure on flowability was also analysed through 3D measurements of void volume and tap density. This study has demonstrated for the first time that XCT provides an invaluable, non-destructive and analytical approach to obtain number- and volume-based particle size distributions of DPI formulations in 3D space, and for unique 3D characterisation of powder micro-structure

Crystallographic Tomography and Molecular Modelling of Structured Organic Polycrystalline Powders

A fundamental understanding of the behaviour of polycrystalline materials, including pharmaceuticals, is vital for control of their physicochemical and crystalline properties, which in turn has the potential to improve drug product development for example. In this work, attenuation X-ray computed tomography (CT) and diffraction contrast tomography (DCT) are combined with molecular modelling to understand the powder packing behaviour and crystal interactions of the organic cubic compound hexamine (hexamethylenetetramine). It is the first application of DCT to polycrystalline organic materials. The crystal morphology is predicted through synthonic modelling, with fully 3D-resolved confirmation of the crystallography of the external {110} facets, edges and corner directions by DCT. Analysis of the powder-bed reveals agglomerate structures and orientational texture, with its chemical origins energetically predicted to be face-to-face in accordance with the experimental data. Finally, measurements of crystal & crystallite interactions provide evidence for different mechanisms of powder bed agglomeration

A Digital Workflow from Crystallographic Structure to Single Crystal Particle Attributes for Predicting the Formulation Properties of Terbutaline Sulfate

A detailed inter-molecular (synthonic) analysis of terbutaline sulfate, an ionic addition salt for inhalation drug formulation, is related to its crystal morphology, and through this to the surface chemistry of the habit faces and surface energy of the whole crystal. Coulombic interactions between the terbutaline cations and sulfate anions contribute 85% of the lattice energy, hydrogen bonding and dispersion interactions contribute 15%. Morphological prediction identifies a plate-like morphology composed of the forms {010}, {100}, {001} and {1¯10} in good agreement with crystals grown from solution. Synthonic modelling of the intermolecular interactions, on a crystal face (hkl)-specific basis, reveals that the surface interactions on the forms with less, relative surface area: {100}, {001} and {1¯10} manifest a greater surface energy, associated, notably, with a greater proportion of polar interactions at these surfaces compared to the {010} surfaces.. The predicted total surface energies and their dispersive contributions are found to be in good agreement with those measured at high surface coverage using inverse gas chromatography (IGC). The modelling approach is complementary to IGC, as it enables surface sites of lower energy to be probed, that would require experimentally unachievable surface coverages. The utility of synthonic modelling, in understanding the surface properties of pharmaceutical materials, is highlighted through a workflow-based pathway for digital drug product design encompassing molecule structure, intermolecular packing, crystal morphology, surface energy and formulation properties

Molecular Synthon Modelling of Inhalation Pharmaceuticals: A Digital Approach to Understanding and Engineering Particle Surface Interactions

Reproduced with permission from Respiratory Drug Delivery 2020, Virginia Commonwealth University and RDD Online.Peer reviewe

On Measuring the Specific Surface Area of inhalation-grade lactose powders

Reproduced with permission from Respiratory Drug Delivery 2020, Virginia Commonwealth University and RDD Online.Peer reviewedFinal Accepted Versio

Multiscale Tomography Probing the Nano-, Micro-, and Meso-scale Resolution of Inhalation Powder Structure

Reproduced with permission from RDD Europe 2019, Virginia Commonwealth University and RDD Online.Understanding the agglomeration behavior of inhaled formulations is essential to ensure consistent aerosolization performance that maximizes drug deposition in the lower respiratory tract. Although many techniques are currently used to characterize critical material attributes (CMAs) such as the particle size distribution (PSD), these techniques suffer from low resolution, image in 2D projections, or are based on shape assumptions. Bearing in mind the importance of the powder microstructure, this work introduces the use of x-ray computed tomography (XCT) as a non- destructive, multiscale technique for characterizing inhalation formulations. Different grades of inhalation and tableting grade lactose have been analyzed using XCT, with distributions for size (volume weighted) and sphericity extracted and compared with laser diffraction and optical microscopy. The three-dimensional information provided from XCT provides a more accurate assessment of powder size and shape, demonstrating the promise for XCT as a valuable powder characterization technique that provides information about the powder microstructure, a descriptor now required from the U.S. Food and Drug Administration (Q3 equivalence).Final Published versio

From Particles to Powders: Digital Approaches to Understand Structure and Powder Flow of Inhaled Formulations

The design of a successful inhaled formulation is a complex project that requires fine tuning of processes and properties to achieve optimal performance. In this work we attempt to provide a summary from the INFORM2020 project of an all-inclusive investigation of inhalation powder blends at various levels of scrutiny. X-Ray Microscopy (XRM) is used to characterize the microstructure and the microstructural changes induced by processing, ring shear tests are used to assess the flowability of the powders and in silico molecular modelling is used to predict the morphology and inter-particle interactions that are critical to efficiently designing superior future formulations. Using this holistic characterization approach to link particle properties to successful inhaled therapies, we hope future dry powder inhalation formulation projects will leave the realm of mysterious art and become firmly science based