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Research & Reviews: A Journal of Drug Design & Discovery Review Article

Formulation Challenges in Long-acting Injectable Small Molecules: Emerging Strategies and Perspectives

  1. Tejaram Choudhary Faculty of Pharmaceutical Science, Mewar University, Gangrar, Chittorgarh 312901
  2. Firoz Ahmed Department of Pharmacy, Faculty of Pharmaceutical Science, Mewar University, Gangrar, Chittorgarh 312901
  3. Tanya Sharma Department of Pharmacy, Faculty of Pharmaceutical Science, Mewar University, Gangrar, Chittorgarh 312901
  4. Kamalesh Mistry Department of Pharmacy, Faculty of Pharmaceutical Science, Mewar University, Gangrar, Chittorgarh 312901

Abstract

Long-acting injectable (LAI) formulations represent a transformative approach in pharmacotherapy, particularly for conditions demanding sustained drug exposure over weeks to months. Although biologics have dominated this space historically, the adaptation of LAI technology to small molecules presents a distinct and complex set of challenges rooted in physicochemical properties, manufacturing scalability, and regulatory expectations. This review systematically addresses the principal formulation barriers encountered in developing LAI small-molecule products, including aqueous solubility limitations, polymorphic instability, particle engineering constraints, and the biological complexities of subcutaneous and intramuscular depots. We critically examine emerging strategies—nanosuspensions, in situ forming implants, lipid-based carriers, cyclodextrin complexation, and polymer–drug conjugates—against the backdrop of clinical relevance and translational feasibility. The roles of excipient selection, sterilization compatibility, and syringeability on depot performance are discussed in depth. Furthermore, pharmacokinetic modeling approaches that facilitate rational formulation design are evaluated. By synthesizing findings across therapeutic areas including psychiatry, infectious disease, oncology, and endocrinology, this review identifies recurring mechanistic patterns and proposes a practical framework for navigating the formulation decision tree in early-stage LAI development. The perspectives presented aim to inform both industrial formulators and academic researchers in accelerating the bench-to-bedside translation of next-generation LAI small-molecule products.

Keywords

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