Particle size matters: The impact of particle size on properties and performance of long-acting injectable crystalline aqueous suspensions.

Over the past few decades, long-acting injectables (LAI) have gained increasing traction to serve the medical needs of patients managing chronic diseases, such as HIV and neurological disorders. Such technologies have the potential to improve patient adherence, reduce adverse effects, and prolong therapeutic efficacy over extended periods ranging from weeks to months. Among various LAI dosage forms (e.g., crystalline aqueous suspensions, implants, and microspheres), LAI crystalline aqueous suspensions are the most frequently used formulation strategy in the past decade. The particle size of the active pharmaceutical ingredient (API) in the LAI aqueous suspension is an important characteristic that affects the performance of the drug product, including stability, pharmacokinetics, sedimentation, resuspendability, and syringeability/injectability. However, there is no specific criteria to determine the optimal particle size distribution to achieve the desired attributes of the LAI aqueous suspension, including those mentioned above. This review aims to inform on this challenge by discussing the interplay of particle size with the key attributes of LAI aqueous suspensions and to provide a multidimensional matrix to facilitate the particle size selection process during product development. We will also discuss formulation strategies and manufacturing technologies that can control particle size within a target range as well as highlight the gaps in our knowledge and toolbox.