Predicting the Strength of Cohesive and Adhesive Interparticle Interactions for Dry Powder Inhalation Blends of Terbutaline Sulfate with α-Lactose Monohydrate.

Grid-based systematic search methods are used to investigate molecule-molecule, molecule-surface, and surface-surface contributions to interparticle interactions in order to identify the crystal faces that most strongly affect particle behavior during powder blend formulation and delivery processes. The model system comprises terbutaline sulfate (TBS) as an active pharmaceutical ingredient (API) and α-form lactose monohydrate (LMH). A combination of systematic molecular modeling and X-ray computed tomography (XCT) is used to determine not only the adhesive and cohesive interparticle energies but, also the agglomeration behavior during manufacturing and de-agglomeration behavior during delivery after inhalation. This is achieved through a detailed examination of the balance between the adhesive and cohesive energies with the XCT results confirming the blend segregation tendencies, through the particle-particle de-agglomeration process. The results reveal that the cohesive interaction energies of TBS-TBS are higher than the adhesive energies between TBS and LMH, but that the cohesive energies of LMH-LMH are the smallest between molecule and molecule, molecule and surface, and surface and surface. This shows how systematic grid-search molecular modeling along with XCT can guide the digital formulation design of inhalation powders in order to achieve optimum aerosolization and efficacy for inhaled medicines. This will lead to faster pharmaceutical design with less variability, higher quality, and enhanced performance.

Microstructural insight into inhalation powder blends through correlative multi-scale X-ray computed tomography.

Dry powder inhalers (DPI) are important for topical drug delivery to the lungs, but characterising the pre-aerosolised powder microstructure is a key initial step in understanding the post-aerosolised blend performance. In this work, we characterise the pre-aerosolised 3D microstructure of an inhalation blend using correlative multi-scale X-ray Computed Tomography (XCT), identifying lactose and drug-rich phases at multiple length scales on the same sample. The drug-rich phase distribution across the sample is shown to be homogeneous on a bulk scale but heterogeneous on a particulate scale, with individual clusters containing different amounts of drug-rich phase, and different parts of a carrier particle coated with different amounts of drug-rich phase. Simple scalings of the drug-rich phase thickness with carrier particle size are used to derive the drug-proportion to carrier particle size relationship. This work opens new doors to micro-structural assessment of inhalation powders that could be invaluable for bioequivalence assessment of dry powder inhalers.

Establishing the suitability of model-integrated evidence to demonstrate bioequivalence for long-acting injectable and implantable drug products: Summary of workshop.

On November 30, 2021, the US Food and Drug administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop titled "Establishing the Suitability of Model-Integrated Evidence (MIE) to Demonstrate Bioequivalence for Long-Acting Injectable and Implantable (LAI) Drug Products." This workshop brought relevant parties from the industry, academia, and the FDA in the field of modeling and simulation to explore, identify, and recommend best practices on utilizing MIE for bioequivalence (BE) assessment of LAI products. This report summerized presentations and panel discussions for topics including challenges and opportunities in development and assessment of generic LAI products, current status of utilizing MIE, recent research progress of utilizing MIE in generic LAI products, alternative designs for BE studies of LAI products, and model validation/verification strategies associated with different types of MIE approaches.

Determining bioequivalence possibilities of long acting injectables through population PK modelling.

Long acting injectables (LAI) products are a popular intervention for treating a number of chronic conditions, with their long drug release reducing the administration frequency and thus improving patient adherence. The extended release, however, can provide a major challenge to bioequivalence (BE) testing since the long absorption half-life results in a long washout period, meaning that a traditional BE study can be many months or years in length. The unique PK profile for LAI products also means that it is critical to have appropriate metrics to summarise the plasma concentration profile. In this work, we use paliperidone as a case study to demonstrate how Population PK modelling can be utilised to explore sensitivity of summary metrics to different products. We also determine a range of products that are bioequivalent after both multiple dosing and single dosing. Finally, we show how the modelling can be used in a (virtual) PK study as an alternative approach to determining bioequivalence. This work demonstrates the potential for Population PK modelling in bioequivalence assessment, opening doors to more streamlined product development.

Size segregation of irregular granular materials captured by time-resolved 3D imaging.

When opening a box of mixed nuts, a common experience is to find the largest nuts at the top. This well-known effect is the result of size-segregation where differently sized 'particles' sort themselves into distinct layers when shaken, vibrated or sheared. Colloquially this is known as the 'Brazil-nut effect'. While there have been many studies into the phenomena, difficulties observing granular materials mean that we still know relatively little about the process by which irregular larger particles (the Brazil nuts) reach the top. Here, for the first time, we capture the complex dynamics of Brazil nut motion within a sheared nut mixture through time-lapse X-ray Computed Tomography (CT). We have found that the Brazil nuts do not start to rise until they have first rotated sufficiently towards the vertical axis and then ultimately return to a flat orientation when they reach the surface. We also consider why certain Brazil nuts do not rise through the pack. This study highlights the important role of particle shape and orientation in segregation. Further, this ability to track the motion in 3D will pave the way for new experimental studies of segregating mixtures and will open the door to even more realistic simulations and powerful predictive models. Understanding the effect of size and shape on segregation has implications far beyond food products including various anti-mixing behaviors critical to many industries such as pharmaceuticals and mining.

New software protocols for enabling laboratory based temporal CT.

Temporal micro-computed tomography (CT) allows the non-destructive quantification of processes that are evolving over time in 3D. Despite the increasing popularity of temporal CT, the practical implementation and optimisation can be difficult. Here, we present new software protocols that enable temporal CT using commercial laboratory CT systems. The first protocol drastically reduces the need for periodic intervention when making time-lapse experiments, allowing a large number of tomograms to be collected automatically. The automated scanning at regular intervals needed for uninterrupted time-lapse CT is demonstrated by analysing the germination of a mung bean (vigna radiata), whilst the synchronisation with an in situ rig required for interrupted time-lapse CT is highlighted using a shear cell to observe granular segregation. The second protocol uses golden-ratio angular sampling with an iterative reconstruction scheme and allows the number of projections in a reconstruction to be changed as sample evolution occurs. This overcomes the limitation of the need to know a priori what the best time window for each scan is. The protocol is evaluated by studying barite precipitation within a porous column, allowing a comparison of spatial and temporal resolution of reconstructions with different numbers of projections. Both of the protocols presented here have great potential for wider application, including, but not limited to, in situ mechanical testing, following battery degradation and chemical reactions.