Grant: INFORM 2020 - Molecules to Manufacture: Processing and Formulation Engineering of Inhalable Nanoaggregates and Microparticles
PI: Professor Darragh Murnane, University of Hertfordshire

Presentation: INFORM 2020: Deconstructing the Role of Powder Agglomerates in Inhaled Powders - pdf
Professor Darragh Murnane, University of Hertfordshire

The state of aggregation of the active pharmaceutical ingredients (APIs) and excipients within inhaled formulations has long been known to direct the success of powder processing as well as product performance. The challenges posed for successful formulation development and manufacture are significant. Small quantities of high surface energy, micron-sized particles have a disproportionate influence on powder behaviour. Material processing frequently induces solid state and formulation instabilities which render reproducible manufacture and aerosolization performance difficult to achieve. INFORM 2020 has sought to address the challenges of inhalation formulations by developing predictive models of formulation behaviour, manufacturing processes and aerosolization events through a variety of crystal, particle, and powder modelling approaches informed by emerging, analytical techniques that probe surface and powder microstructure.


Question (Simon Gibbon): @Parmesh / @ Darragh how complex is identifying particles in the X-ray CT?  Has the process been automated to get statistics by looking at a number of different unique samples?

Response (Darragh Murnane): Hi Simon - sorry I couldn't give much more information than that for the moment. But yes - it can be run by automated analysis, but it does require some manual work at the moment. The statistics can be generated automatically, but there does still need to be some work done manually on thresholding to identify the individual particles.

Response (Parmesh Gajjar): Just to build on Darragh's answer, as we move through more samples, we will develop the confidence to have a completely automated system

Question (Jin Sun): @Darragh How is the x-ray CT sizing performance compare to other methods, e.g. dynamic light scattering?

Response (Darragh Murnane): Hi Jin - the Xray sizing compares very well to laser diffraction analysis, which is the standard technique on this scale of size. We can't use DLS for micron size particles. We did publish the comparison in our recent paper.

Question (Philip Gill): @Darragh You discussed your spacial resolution on CT analysis. But how good is the contrast resolution at looking into the agglomerates? Can you distinguish similar materials?

Response (Darragh Murnane): Hi Phil - yes we can identify different chemical species based on the xray physics. We also have seen very different particle behaviour between different materials.

Question (Simon Gibbon): @Darragh with the wide range of particle sizes seen in your agglomerates and limited X-ray CT resolution - what would a factor of 10 in resolution do to the calculated porosity?  Or probably the right question is how well does porosity calculated from X-ray CT agree with porosity measured by other methods?

Response (Darragh Murnane): Simon - the porosity is a very moot point - it depends on what we're looking at. We have seen excellent correlation to tap densitometry measurements of bulk powder density. But there are some real issues with other techniques for measuring agglomerate porosity (e.g. mercury intrusion). But we feel since we're measuring volume scales of powders which are significantly larger than the scale of the individual particles within the agglomerate, and because we clearly define the volume in which we measure those particles/void volumes, that we probably provide a more accurate density value than the existing techniques for 'disruptable' (i.e. non-fused) agglomerates of microparticles.

Question (Tim Akerman): @Darragh what is the confidence level for those distribution ranges?

Response (Darragh Murnane): Tim - good question. We count 1000s of particles, so the confidence level is excellent. I can't give you a specific percentage. But it's true to say from our comparison against laser diffraction, that the confidence limits of the sizing are tight enough for sampling variation to be more important. This is similar to the benchmark laser diffraction.

Follow up question (Tim Akerman): @Darragh thanks for your answer; given that sample variation is the larger inconsistency have you used intra-sample variation or inter-sample variation to determine the appropriate sample size for reproducibility of results?

Response (Darragh Murnane): Tim - sample variability: We take a standard sample for inhalation formulations (~10-20 mg) and we image multiple sections through that sample. our next work (which has been interrupted by Covid shutdowns) was using the XRCT to look at intra-sample and inter-sample variability. However, our intrasample variability is within the limits of the comparator techniques.

Question (Andrew Bayly): Do electrostatics play a role in dispersion? What is the smallest particle you can detect when you look at mixture of the lactose and API?

Response (Darragh Murnane): Hi Andrew - Electrostatics: Most materials are allowed to relax over time before formulation. Electrostatics may emerge during the blending process from friction, but before aerosolization the materials are allowed to relax. Yes statics probably do affect uniformity of distribution, but will dissipate before shipping or testing. Any static charge is typically generated during the aersolisation event by triboelectrification.

Poster: On measuring the specific surface area of inhalation-grade lactose powders - pdf
Dr Ioanni Danal Styliari, University of Hertfordshire

Poster: Experimental and numerical analysis of the flow properties of different lactose grades - pdf
Xizhong Chen, University of Cambridge

Poster: A digital approach from crystallographic structure to particle attributes for predicting the formulation properties of inhalation pharmaceuticals - pdf
Hien Nguyen, University of Leeds

Poster: Molecular modelling metered dose inhaler suspension formulations - pdf
Vivian Walter Barron, University of Leeds

Poster: X-ray microscopy for inhalation formulations - pdf
Parmesh Gajjar, University of Manchester

The advent of x-ray optics has allowed higher resolution and improved contrast on laboratory x-ray computed tomography machines. In particular, this has allowed us to examine the microstructure of (dry powder) inhalation formulations in the INFORM2020 project. This poster presents a summary of work including characterisation of carrier lactose, intra-agglomerate quantitative analysis for micronised lactose and examination of drug-carrier blends.

RSC FST Future Formulation IV - The Conference

Grant Page: Predictive formulation of high-solid-content complex dispersions
PIs: Dr Jin Sun, University of Edinburgh & Dr Mark Haw, University of Strathclyde

Grant Page: Virtual Formulation Laboratory for prediction and optimisation of manufacturability of advanced solids based formulations
PI: Dr Csaba Sinka, University of Leicester

Grant Page: Evaporative Drying of Droplets and the Formation of Micro-structured and Functional Particles and Films
PI: Professor Colin Bain, Durham University

Grant Page: Enabling rapid liquid and freeze-dried formulation design for the manufacture and delivery of novel biopharmaceuticals
PIs: Dr Robin Curtis, The University of Manchestr & Professor Paul Dalby, University College London

Grant Page: Complex ORAL health products (CORAL): Characterisation, modelling and manufacturing challenges
PI: Professor Panagiota Angeli, University College London

Grant Page: Formulation for 3D printing: Creating a plug and play platform for a disruptive UK industry
PI: Professor Ricky Wildman, University of Nottingham

Grant Page: INFORM 2020 - Molecules to Manufacture: Processing and Formulation Engineering of Inhalable Nanoaggregates and Microparticles
PI: Professor Darragh Murnane, University of Hertfordshire