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

Year : 2026 | Volume : 13 | 02 | Page :
    By

    Tejaram Choudhary,

  • Firoz Ahmed,

  • Tanya Sharma,

  • Kamalesh Mistry,

  1. Research Scholar, Faculty of Pharmaceutical Science, Mewar University, Gangrar, Chittorgarh 312901, Rajasthan, India
  2. Assistant Professor, Department of Pharmacy, Faculty of Pharmaceutical Science, Mewar University, Gangrar, Chittorgarh 312901, Rajasthan, India
  3. Assistant Professor, Department of Pharmacy, Faculty of Pharmaceutical Science, Mewar University, Gangrar, Chittorgarh 312901, Rajasthan, India
  4. Associate Professor, Department of Pharmacy, Faculty of Pharmaceutical Science, Mewar University, Gangrar, Chittorgarh 312901, Rajasthan, India

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: Long-acting injectables; depot formulations; nanosuspensions; in situ forming systems; sustained release; small molecules; particle engineering; pharmacokinetics

How to cite this article:
Tejaram Choudhary, Firoz Ahmed, Tanya Sharma, Kamalesh Mistry. Formulation Challenges in Long-acting Injectable Small Molecules: Emerging Strategies and Perspectives. Research & Reviews: A Journal of Drug Design & Discovery. 2026; 13(02):-.
How to cite this URL:
Tejaram Choudhary, Firoz Ahmed, Tanya Sharma, Kamalesh Mistry. Formulation Challenges in Long-acting Injectable Small Molecules: Emerging Strategies and Perspectives. Research & Reviews: A Journal of Drug Design & Discovery. 2026; 13(02):-. Available from: https://journals.stmjournals.com/rrjoddd/article=2026/view=242719


References

1. Velligan, D. I., Weiden, P. J., Sajatovic, M., Scott, J., Carpenter, D., Ross, R., & Docherty, J. P. (2009). The expert consensus guideline series: Adherence problems in patients with serious and persistent mental illness. Journal of Clinical Psychiatry, 70(Suppl. 4), 1–46. https://doi.org/10.4088/JCP.7090su1cj
2. Owen, A., Rannard, S., & Chichester, C. (2016). Formulation challenges for human immunodeficiency virus (HIV) long acting (LA) patient derived antiretrovirals. Advanced Drug Delivery Reviews, 103, 56–67. https://doi.org/10.1016/j.addr.2016.01.010
3. Citrome, L. (2014). Activating and sedating adverse effects of second-generation antipsychotics in the treatment of schizophrenia and major depressive disorder. Journal of Clinical Psychopharmacology, 34(2), 170–175. https://doi.org/10.1097/JCP.0000000000000089
4. Rabinow, B. E. (2004). Nanosuspensions in drug delivery. Nature Reviews Drug Discovery, 3(9), 785–796. https://doi.org/10.1038/nrd1494
5. Larsen, C., Larsen, S. W., Jensen, H., Yaghmur, A., & Østergaard, J. (2009). Role of in vitro release models in formulation development and quality control of parenteral depots. Expert Opinion on Drug Delivery, 6(12), 1283–1295. https://doi.org/10.1517/17425240903307431
6. Bernstein, J. (2002). Polymorphism in molecular crystals. Oxford University Press.
7. Gopal, S., Hough, D., Xu, H., Lull, J. M., Gassmann-Mayer, C., Remmerie, B. M., Eerdekens, M., & Brown, D. (2010). Efficacy and safety of paliperidone palmitate monthly injectable once-monthly formulation in schizophrenia. Schizophrenia Research, 120(1–3), 26–35. https://doi.org/10.1016/j.schres.2010.03.012
8. Bhatt, D. K., Bhikha, R., & Bhatt, K. (2019). Factors affecting drug release from injectable depot formulations. Drug Development and Industrial Pharmacy, 45(3), 347–357. https://doi.org/10.1080/03639045.2018.1541836
9. Sjöström, B., Kälén, A., Engström, S., & Bergenholtz, J. (1993). The influence of lipid composition on the stability of submicron emulsions after heat sterilization. International Journal of Pharmaceutics, 93(1–3), 89–101. https://doi.org/10.1016/0378-5173(93)90167-I
10. Müller, R. H., Gohla, S., & Keck, C. M. (2011). State of the art of nanocrystals – Special features, production, nanotoxicology aspects and intracellular delivery. European Journal of Pharmaceutics and Biopharmaceutics, 78(1), 1–9. https://doi.org/10.1016/j.ejpb.2011.01.007
11. Van Eerdenbrugh, B., Van den Mooter, G., & Augustijns, P. (2008). Top-down production of drug nanocrystals: Nanosuspension stabilization, miniaturization and transformation into solid products. International Journal of Pharmaceutics, 364(1), 64–75. https://doi.org/10.1016/j.ijpharm.2008.07.023
12. Margolis, D. A., Gonzalez-Garcia, J., Stellbrink, H.-J., Eron, J. J., Yazdanpanah, Y., Podzamczer, D., Lutz, T., Angel, J. B., Richmond, G. J., Clotet, B., Gutierrez, F., Sloan, L., Clair, M. S., Murray, M., Ford, S. L., Mrus, J., Patel, P., Crauwels, H., Griffith, S. K., & Spreen, W. R. (2017). Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet, 390(10101), 1499–1510. https://doi.org/10.1016/S0140-6736(17)31917-7
13. Kempe, S., & Mäder, K. (2012). In situ forming implants – An attractive formulation principle for parenteral depot formulations. Journal of Controlled Release, 161(2), 668–679. https://doi.org/10.1016/j.jconrel.2012.04.016
14. Bhardwaj, U., & Burgess, D. J. (2010). A novel USP apparatus 4 based release testing method for dispersed systems. International Journal of Pharmaceutics, 388(1–2), 287–294. https://doi.org/10.1016/j.ijpharm.2009.12.050
15. Packhaeuser, C. B., Schnieders, J., Oster, C. G., & Kissel, T. (2004). In situ forming parenteral drug delivery systems: An overview. European Journal of Pharmaceutics and Biopharmaceutics, 58(2), 445–455. https://doi.org/10.1016/j.ejpb.2004.03.003
16. Muchow, M., Maincent, P., & Müller, R. H. (2008). Lipid nanoparticles with a solid matrix (SLN, NLC, LDC) for oral drug delivery. Drug Development and Industrial Pharmacy, 34(12), 1394–1405. https://doi.org/10.1080/03639040802130061
17. Mehnert, W., & Mäder, K. (2001). Solid lipid nanoparticles: Production, characterization and applications. Advanced Drug Delivery Reviews, 47(2–3), 165–196. https://doi.org/10.1016/S0169-409X(01)00105-3
18. Danhier, F., Ansorena, E., Silva, J. M., Coco, R., Le Breton, A., & Préat, V. (2012). PLGA-based nanoparticles: An overview of biomedical applications. Journal of Controlled Release, 161(2), 505–522. https://doi.org/10.1016/j.jconrel.2012.01.043
19. Park, T. G. (1995). Degradation of poly(lactic-co-glycolic acid) microspheres: Effect of copolymer composition. Biomaterials, 16(15), 1123–1130. https://doi.org/10.1016/0142-9612(95)93575-X
20. Loftsson, T., & Brewster, M. E. (2010). Pharmaceutical applications of cyclodextrins: Basic science and product development. Journal of Pharmacy and Pharmacology, 62(11), 1607–1621. https://doi.org/10.1111/j.2042-7158.2010.01030.x
21. Stella, V. J., & He, Q. (2008). Cyclodextrins. Toxicologic Pathology, 36(1), 30–42. https://doi.org/10.1177/0192623307310945
22. Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., & Savolainen, J. (2008). Prodrugs: Design and clinical applications. Nature Reviews Drug Discovery, 7(3), 255–270. https://doi.org/10.1038/nrd2468
23. Sionkowska, A. (2011). Current research on the blends of natural and synthetic polymers as new biomaterials. Progress in Polymer Science, 36(9), 1254–1276. https://doi.org/10.1016/j.progpolymsci.2011.05.003
24. U.S. Food and Drug Administration. (2014). Guidance for industry: Immunogenicity assessment for therapeutic protein products. U.S. Department of Health and Human Services. https://www.fda.gov/media/85017/download
25. Burgess, D. J., Crommelin, D. J. A., Hussain, A. S., & Chen, M.-L. (2004). Assuring quality and performance of sustained and controlled release parenterals: EUFEPS workshop report. AAPS PharmSciTech, 5(1), Article 14. https://doi.org/10.1208/pt050114
26. Derendorf, H., & Meibohm, B. (1999). Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: Concepts and perspectives. Pharmaceutical Research, 16(2), 176–185. https://doi.org/10.1023/A:1011907920641
27. Kagan, L., Turner, M. R., Balu-Iyer, S. V., & Mager, D. E. (2012). Subcutaneous absorption of monoclonal antibodies: Role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats. Pharmaceutical Research, 29(2), 490–499. https://doi.org/10.1007/s11095-011-0578-3
28. Fonte, P., Soares, S., Costa, A., das Neves, J., Seabra, V., Reis, S., & Sarmento, B. (2012). Effect of cryoprotectants on the porosity and stability of freeze-dried PLGA and chitosan nanoparticles. Biomatter, 2(4), 329–339. https://doi.org/10.4161/biom.23246
29. U.S. Food and Drug Administration. (2019). Exposure-response relationships – Study design, data analysis, and regulatory applications. U.S. Department of Health and Human Services. https://www.fda.gov/media/88887/download
30. Citrome, L., Stauffer, V. L., Chen, L., Tsai, L. F., Lord, B., & Jakab, M. S. (2009). Olanzapine long-acting injection: A review of first published data. Journal of Clinical Psychopharmacology, 29(5), 432–437. https://doi.org/10.1097/JCP.0b013e3181b57f71
31. Lienhardt, C., Nahid, P., Rich, M. L., Bhargava, A., Balasegaram, M., Bansbach, C., Baran, D., Barry, C. E., Bhargava, A., Burzynski, J., Cattamanchi, A., Chaisson, R. E., Churchyard, G., Cox, H., Daley, C. L., Dannenberg, A. M., Farrar, J., Ginsberg, A. M., Gupta, R., … Wells, W. A. (2012). Target regimen profiles for treatment of tuberculosis: A WHO document. European Respiratory Journal, 39(3), 765–768. https://doi.org/10.1183/09031936.00166311

Ahead of Print Subscription Review Article
Volume 13
02
Received 07/04/2026
Accepted 19/04/2026
Published 02/05/2026
Publication Time 25 Days
1

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