Solid Lipid Nanoparticles: Fundamentals, Design and Applications
Chapter 12 - Scale-Up, Manufacturing, and Regulatory Considerations for Solid Lipid Nanoparticles
Surendra Agrawal, Pravina N. Gurjar, Deepak Khobragade
Abstract:
Solid Lipid Nanoparticles (SLNs) have emerged as an important nanocarrier technology in drug delivery, celebrated for their compatibility with biological systems, enhanced bioavailability, and ability to regulate drug release effectively. The journey of SLN formulations moving from the realm of laboratory prototypes to becoming commercially viable pharmaceutical medicines involves navigating a series of intricate challenges. The chapter provides a comprehensive exploration of the technological, manufacturing, and regulatory aspects that are vital for effectively scaling up and applying SLNs in an industrial context. Challenges in scaling up involve maintaining consistency across batches, safeguarding crucial quality attributes like particle size, zeta potential, and encapsulation efficiency, and adapting laboratory techniques to larger-scale processes such as high-pressure homogenization and spray drying. The importance of applying Design of Experiments (DoE) and Process Analytical Technology (PAT) is highlighted as essential for enhancing manufacturing parameters and ensuring product consistency. Furthermore, key aspects such as the choice of raw materials, the setup of equipment, the management of temperature and sterility, and the processes of quality testing are explored within the context of production that adheres to GMP standards. This chapter outlines the current regulatory framework set forth by authorities like the USFDA and EMA, emphasizing the importance of quality by design (QbD), risk assessment, and the need to adhere to ICH recommendations regarding stability, documentation, and safety evaluation. The absence of clear regulatory standards for nanomedicine necessitates a tailored, individualized approval process for each case. This chapter concludes by emphasizing future perspectives that reveal the importance of cohesive regulatory standards, the integration of AI-driven process controls, and the advancement of continuous production for SLNs. The insights shared serve as a valuable resource for formulation scientists, process engineers, and regulatory experts working within the nanopharmaceutical field.
Keywords: Solid Lipid Nanoparticles (SLNs), Scale-Up Techniques, Quality by Design (QbD), Regulatory Compliance
References:
[1] Mohammed HA, Khan RA, Singh V, Yusuf M, Akhtar N, Sulaiman GM, et al. Solid lipid nanoparticles for targeted natural and synthetic drugs delivery in high-incidence cancers, and other diseases: Roles of preparation methods, lipid composition, transitional stability, and release profiles in nanocarriers’ development. Nanotechnology reviews. 2023;12(1):20220517.
[2] Mirchandani Y, Patravale VB. Solid lipid nanoparticles for hydrophilic drugs. Journal of controlled release. 2021;335:457-64.
[3] Subroto E, Andoyo R, Indiarto R. Solid lipid nanoparticles: Review of the current research on encapsulation and delivery systems for active and antioxidant compounds. Antioxidants. 2023;12(3):633.
[4] Queiroz MdCV, Muehlmann LA. Characteristics and preparation of solid lipid nanoparticles and nanostructured lipid carriers. Journal of Nanotheranostics. 2024;5(4):188-211.
[5] Harini A, Perumal I. Polymeric nanomaterials as a drug delivery system for anticancer and antibacterial infections: a review. RSC advances. 2025;15(39):32572-92.
[6] Khairnar SV, Pagare P, Thakre A, Nambiar AR, Junnuthula V, Abraham MC, et al. Review on the scale-up methods for the preparation of solid lipid nanoparticles. Pharmaceutics. 2022;14(9):1886.
[7] Sivadasan D, Sultan MH, Madkhali O, Almoshari Y, Thangavel N. Polymeric lipid hybrid nanoparticles (plns) as emerging drug delivery platform—A comprehensive review of their properties, preparation methods, and therapeutic applications. Pharmaceutics. 2021;13(8):1291.
[8] Sammasagi SS, Sutar KP, Hooli S. Scale-up and quality control challenges in the industrial manufacturing of nanoformulations: current trends and future perspectives. IJSAT-International Journal on Science and Technology. 2025;16(2).
[9] Campos J, Severino P, Santini A, Silva A, Shegokar R, Souto S, et al. Solid lipid nanoparticles (SLN): prediction of toxicity, metabolism, fate and physicochemical properties. Nanopharmaceuticals. 2020:1-15.
[10] Ergin AD, Uner B. Quality by design for parenteral formulations. Introduction to Quality by Design (QbD) From Theory to Practice: Springer; 2024. p. 217-42.
[11] Rout S, Sevgili SŞ, Srivastav PP, Falsafi SR. Scale up and industrialization of nonthermal processing approaches: current state, challenges, limitations and future trends. Non-thermal Processing of Major Food Macromolecules: Elsevier; 2025. p. 381-96.
[12] Abdelmonem R, Ayman M, Ezzat Y, Mohamed H, Abdelzaher A, Abdelkhalek M, et al. Advancing nanoparticle production: scaling up techniques, challenges, and future perspectives in pharmaceutical applications. Journal of Pharmaceutical Sciences and Drug Manufacturing-Misr University for Science and Technology. 2025;2(2):26-39.
[13] Sathiyapriyan P, Mukherjee S, Vogel T, Essen LO, Boerema D, Vey M, et al. Current PAT Landscape in the Downstream Processing of Biopharmaceuticals. Analytical Science Advances. 2025;6(1):e70013.
[14] Lee SL, O’Connor TF, Yang X, Cruz CN, Chatterjee S, Madurawe RD, et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. Journal of Pharmaceutical Innovation. 2015;10(3):191-9.
[15] Kadam T, Agrawal S, Shetty S. Novel nanostructured lipid carriers with lurasidone hydrochloride for intranasal administration for improved bioavailability. Therapeutic Delivery. 2025;16(5):419-29.
[16] Kardani SL. Nanocarrier-based formulations: regulatory challenges, ethical and safety considerations in pharmaceuticals. Asian Journal of Pharmaceutics (AJP). 2024;18(02).
[17] Leghari QA, Anwar NT, Syed Y, Shuja AA, Ali M. Ensuring Pharmaceutical Quality: The Role of Stability Studies and Regulatory Guidelines: A Review. Indus Journal of Bioscience Research. 2025;3(3):112-22.
[18] Chountoulesi M, Naziris N, Pippa N, Demetzos C. The significance of drug-to-lipid ratio to the development of optimized liposomal formulation. Journal of liposome research. 2018;28(3):249-58.
[19] Pandey S, Nayak P, Malaiya A, Paliwal R, Alam MI, Kashid S, et al. Colloidal Drug Delivery System: An Overview. Novel Carrier Systems for Targeted and Controlled Drug Delivery. 2024:339-90.
[20] Rosenblatt KM, Bunjes H. Evaluation of the drug loading capacity of different lipid nanoparticle dispersions by passive drug loading. European Journal of Pharmaceutics and Biopharmaceutics. 2017;117:49-59.
[21] Sinha S, Ravi PR, Somvanshi M, Rashmi S. Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia. Discover Nano. 2024;19(1):218.
[22] Chen D, Yu Y, Lee YY, Chen N, Wang Y, Qiu C. Effect of surfactants on the interfacial behaviors of diacylglycerol-based solid lipid nanoparticles and physical stability of W/O emulsion. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2023;675:132070.
[23] Badmus SO, Amusa HK, Oyehan TA, Saleh TA. Environmental risks and toxicity of surfactants: overview of analysis, assessment, and remediation techniques. Environmental Science and Pollution Research. 2021;28(44):62085-104.
[24] Ghorab M, Gardouh A, Gad S. Effect of viscosity, surfactant type and concentration on physicochemical properties of solid lipid nanoparticles. Int J Pharm Pharm Sci. 2015;7(3):145-53.
[25] Khadka P, Ro J, Kim H, Kim I, Kim JT, Kim H, et al. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian journal of pharmaceutical sciences. 2014;9(6):304-16.
[26] Duong V-A, Nguyen T-T-L, Maeng H-J. Preparation of solid lipid nanoparticles and nanostructured lipid carriers for drug delivery and the effects of preparation parameters of solvent injection method. Molecules. 2020;25(20):4781.
[27] Battaglia L, Gallarate M. Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery. Expert opinion on drug delivery. 2012;9(5):497-508.
[28] Ife AF, Harding IH, Shah RM, Palombo EA, Eldridge DS. Effect of pH and electrolytes on the colloidal stability of stearic acid–based lipid nanoparticles. Journal of Nanoparticle Research. 2018;20(12):318.
[29] Ball RL, Bajaj P, Whitehead KA. Achieving long-term stability of lipid nanoparticles: examining the effect of pH, temperature, and lyophilization. International journal of nanomedicine. 2017:305-15.
[30] Subramaniam B, Siddik ZH, Nagoor NH. Optimization of nanostructured lipid carriers: Understanding the types, designs, and parameters in the process of formulations. Journal of nanoparticle research. 2020;22(6):141.
[31] Garcês A, Amaral M, Lobo JS, Silva AC. Formulations based on solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for cutaneous use: A review. European Journal of Pharmaceutical Sciences. 2018;112:159-67.
[32] Bnyan R, Khan I, Ehtezazi T, Saleem I, Gordon S, O’Neill F, et al. Surfactant effects on lipid-based vesicles properties. Journal of pharmaceutical sciences. 2018;107(5):1237-46.
[33] Vinchhi P, Patel JK, Patel MM. High-pressure homogenization techniques for nanoparticles. Emerging Technologies for Nanoparticle Manufacturing: Springer; 2021. p. 263-85.
[34] Mistry PH, Mohapatra SK, Dash AK. Effect of high-pressure homogenization and stabilizers on the physicochemical properties of curcumin-loaded glycerol monooleate/chitosan nanostructures. Nanomedicine. 2012;7(12):1863-76.
[35] Bhattacharjee S, Debnath R, Kumar SA, Saha A, Saha S, Debnath S. A technical review: solid-lipid nanoparticle (SLN), their characteristics and their preparation. Asian journal of pharmaceutical research and development. 2020;8(3):185-9.
[36] Yadav V, AlokMahor S, Alok S, AmitaVerma A, Kumar N, Kumar S. Solid lipid nanoparticles (sln): formulation by high pressure homogenization. World J Pharm Pharm Sci. 2014;3(11):1200-13.
[37] Khishvand MA, Yeganeh EM, Zarei M, Soleimani M, Mohammadi M, Mahjub R. Development, Statistical Optimization, and Characterization of Resveratrol‐Containing Solid Lipid Nanoparticles (SLNs) and Determination of the Efficacy in Reducing Neurodegenerative Symptoms Related to Alzheimer’s Disease: In Vitro and In Vivo Study. BioMed Research International. 2024;2024(1):7877265.
[38] Kluge J, Muhrer G, Mazzotti M. High pressure homogenization of pharmaceutical solids. The Journal of Supercritical Fluids. 2012;66:380-8.
[39] Raximberdiyeva Z, Akhrarova S, Shodikulova G, Tuychibekov S, Jalilov O, Nasullayeva K, et al. Dual-Encapsulation of Paclitaxel and Quercetin in Solid Lipid Nanoparticles for Enhanced Pulmonary Cancer Therapy: In Vitro and In Vivo Evaluation. Journal of Nanostructures. 2025;15(3):1457-62.
[40] Ding Y, Kan J. Optimization and characterization of high pressure homogenization produced chemically modified starch nanoparticles. Journal of Food Science and Technology. 2017;54(13):4501-9.
[41] Garud A, Singh D, Garud N. Solid lipid nanoparticles (SLN): method, characterization and applications. International Current Pharmaceutical Journal. 2012;1(11):384-93.
[42] Shah RM, Malherbe F, Eldridge D, Palombo EA, Harding IH. Physicochemical characterization of solid lipid nanoparticles (SLNs) prepared by a novel microemulsion technique. Journal of colloid and interface science. 2014;428:286-94.
[43] Jacob S, Nair A, Shah J, Gupta S, Boddu S, Sreeharsha N, et al. Lipid nanoparticles as a promising drug delivery carrier for topical ocular therapy—an overview on recent advances. Pharmaceutics 2022; 14 (3): 533. s Note: MDPI stays neu-tral with regard to jurisdictional claims in …; 2022.
[44] Korolev D, Shumilo M, Shulmeyster G, Krutikov A, Golovkin A, Mishanin A, et al. Hemolytic activity, cytotoxicity, and antimicrobial effects of human albumin-and polysorbate-80-coated silver nanoparticles. Nanomaterials. 2021;11(6):1484.
[45] Pal N, Alzahid Y, AlSofi AM, Ali M, Hoteit H. Review on microemulsions for conformance improvement technology: Fundamentals, design considerations, and perspectives. Energy & Fuels. 2023;37(2):858-75.
[46] Lee S-E, Lee J-K, Jang W-S, Kim T-H, Tunsirikongkon A, Choi J-S, et al. Enhancement of stability and controlled drug release of lipid nanoparticles by modified solvent-evaporation method. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2016;508:294-300.
[47] Chaudhary SA, Patel DM, Patel JK, Patel DH. Solvent emulsification evaporation and solvent emulsification diffusion techniques for nanoparticles. Emerging technologies for nanoparticle manufacturing: Springer; 2021. p. 287-300.
[48] Akbari Z, Amanlou M, Karimi-Sabet J, Golestani A, Shariaty Niassar M. Application of supercritical fluid technology for preparation of drug loaded solid lipid nanoparticles. International journal of nanoscience and nanotechnology. 2020;16(1):13-33.
[49] Majeed M, Rather MA. Enhancing shelf life and bioavailability of vitamin D through encapsulation: A comprehensive review. Food Biophysics. 2025;20(1):15.
[50] Akbari Z, Amanlou M, Karimi-Sabet J, Golestani A, Niassar MS. Preparation and characterization of solid lipid nanoparticles through rapid expansion of supercritical solution. Ind J Pharm Sci Tech. 2014;5(5):1693-704.
[51] Tomou E-M, Papakyriakopoulou P, Saitani E-M, Valsami G, Pippa N, Skaltsa H. Recent advances in nanoformulations for quercetin delivery. Pharmaceutics. 2023;15(6):1656.
[52] Tan KT, Lee KT. A review on supercritical fluids (SCF) technology in sustainable biodiesel production: Potential and challenges. Renewable and Sustainable Energy Reviews. 2011;15(5):2452-6.
[53] John R, Monpara J, Swaminathan S, Kalhapure R. Chemistry and art of developing lipid nanoparticles for biologics delivery: focus on development and scale-up. Pharmaceutics. 2024;16(1):131.
[54] Aguiam N, Moura L, Oliveira M, Florindo H, Lopes J. Process analytics for the manufacturing of nanomedicines: Challenges and opportunities. Artificial intelligence for drug product lifecycle applications. 2025:169-203.
[55] Hock SC, Siang TK, Wah CL. Continuous manufacturing versus batch manufacturing: benefits, opportunities and challenges for manufacturers and regulators. Generics and Biosimilars Initiative Journal. 2021;10(1):1-14.
[56] Andonova V, Peneva P. Characterization methods for solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). Current pharmaceutical design. 2017;23(43):6630-42.
[57] Jourghanian P, Ghaffari S, Ardjmand M, Haghighat S, Mohammadnejad M. Sustained release curcumin loaded solid lipid nanoparticles. Advanced pharmaceutical bulletin. 2016;6(1):17.
[58] Dubes A, Parrot-Lopez H, Abdelwahed W, Degobert G, Fessi H, Shahgaldian P, et al. Scanning electron microscopy and atomic force microscopy imaging of solid lipid nanoparticles derived from amphiphilic cyclodextrins. European journal of pharmaceutics and biopharmaceutics. 2003;55(3):279-82.
[59] Shah R, Eldridge D, Palombo E, Harding I. Optimisation and stability assessment of solid lipid nanoparticles using particle size and zeta potential. Journal of physical science. 2014;25(1).
[60] zur Mühlen A, Schwarz C, Mehnert W. Solid lipid nanoparticles (SLN) for controlled drug delivery–drug release and release mechanism. European journal of pharmaceutics and biopharmaceutics. 1998;45(2):149-55.
[61] Freitas C, Müller R. Correlation between long-term stability of solid lipid nanoparticles (SLN™) and crystallinity of the lipid phase. European journal of pharmaceutics and biopharmaceutics. 1999;47(2):125-32.
[62] Zielińska A, Soles BB, Lopes AR, Vaz BF, Rodrigues CM, Alves TF, et al. Nanopharmaceuticals for eye administration: Sterilization, depyrogenation and clinical applications. Biology. 2020;9(10):336.
[63] Paliwal R, Paliwal SR, Kenwat R, Kurmi BD, Sahu MK. Solid lipid nanoparticles: A review on recent perspectives and patents. Expert opinion on therapeutic patents. 2020;30(3):179-94.
[64] Agrawal S, Vaidya S, Patel J, Jirvankar P, Gurjar P. Challenges and Pathways in Regulating Next-Gen Biological Therapies. Current Pharmaceutical Biotechnology. 2025.
[65] Souto EB, Silva GF, Dias-Ferreira J, Zielinska A, Ventura F, Durazzo A, et al. Nanopharmaceutics: Part I—Clinical trials legislation and good manufacturing practices (GMP) of nanotherapeutics in the EU. Pharmaceutics. 2020;12(2):146.
[66] O’Brien Laramy M, Foley DA, Pak RH, Lewis JA, McKinney E, Egan PM, et al. Chemistry, manufacturing and controls strategies for using novel excipients in lipid nanoparticles. Nature Nanotechnology. 2025;20(3):331-44.