Formulations at the Nanoscale: Multi-dimensional Electron Diffraction of Long-Acting Injectable, Cabotegravir

Abstract Long-acting injectables (LAIs) are pharmaceutical formulations designed for slow, sustained release of medication, allowing for less frequent dosing and improved adherence. Cabotegravir-LA is an intramuscular injectable form of the antiretroviral drug cabotegravir (GSK1265744) for Human Immunodeficiency Virus prevention, in which nanocrystallites of cabotegravir are suspended in an aqueous solution. Particle size plays a major role in determining the rate of drug release; in Cabotegravir-LA, cabotegravir crystals are nano-milled to achieve the desired median particle size. In this work, we apply multi-dimensional electron diffraction to an LAI formulation of cabotegravir. Firstly, we use 3D electron diffraction to solve the structure of cabotegravir from a microcrystal, demonstrating its structure within the formulation is consistent with the single-crystal X-ray diffraction structure. Secondly, 3D electron diffraction is combined with high-angle annular dark field imaging to relate the shape of cabotegravir particles to its crystal structure. We compare these experimental observations to crystal growth and morphology models. Finally, we use 4D-scanning transmission electron microscopy to observe dislocations in the crystals. These insights could, in future, enable further optimization of the product formulation by engineering nanoscale structural and microstructural features.