INTRODUCTION

Nanotechnology has markedly advanced modern drug delivery by enabling the development of nanoscale carrier systems capable of improving drug solubility, stability, targeting efficiency, and therapeutic performance. Among these systems, solid lipid nanoparticles (SLNs) have received sustained scientific interest over the past three decades as lipid-based nanocarriers composed of biocompatible and physiologically acceptable excipients. Their ability to enhance the bioavailability of poorly water-soluble drugs addresses a persistent challenge in pharmaceutical development, as it is estimated that more than 40% of marketed drugs and nearly 90% of drug candidates in development exhibit low aqueous solubility [1, 2].

SLNs were introduced in the early 1990s as an alternative to polymeric nanoparticles, with the aim of overcoming limitations associated with polymer-related toxicity, degradation byproducts, and regulatory complexity. By combining advantages of polymeric nanoparticles (controlled release) and liposomes (biocompatibility), while reducing their respective drawbacks, SLNs have emerged as a promising delivery platform suitable for a broad range of therapeutic agents [3, 4]. Consequently, research on SLNs has expanded significantly, with continuous growth in publications focusing on formulation strategies, route-specific delivery, and therapeutic applications.

Structurally, SLNs are composed of solid lipids such as triglycerides, fatty acids, waxes, and glyceride mixtures that remain solid at both room and physiological temperatures. This solid-state lipid matrix enhances nanoparticle stability and protects encapsulated drugs from chemical and enzymatic degradation. Typically ranging from 50 to 1000 nm in size, SLNs facilitate controlled drug release and improved interaction with biological membranes, enabling enhanced transport across physiological barriers compared with conventional dosage forms [5].

A key advantage of SLNs is their adaptability to multiple routes of administration, including oral, parenteral, transdermal, ocular, and pulmonary delivery. This versatility allows SLNs to be tailored for site-specific, sustained, or targeted drug delivery, expanding their potential applications across diverse therapeutic areas [6]. In oral delivery, for example, SLNs may improve drug absorption through lymphatic uptake, endocytosis, and paracellular transport, while certain lipid components and surfactants can modulate efflux transporters such as P-glycoprotein. Surface modification with polymers such as chitosan further enhances mucoadhesion and oral bioavailability [7–10].

Despite extensive preclinical research and promising therapeutic outcomes, the successful clinical and industrial translation of SLNs remains limited. Several critical challenges persist, including lipid polymorphism, phase separation, sterilization difficulties, long-term stability, and batch-to-batch variability. These factors directly influence drug loading, release behavior, safety, and reproducibility. In addition, large-scale production of SLNs requires precise control of process parameters to ensure consistent particle size distribution, drug encapsulation efficiency, and regulatory compliance. Although techniques such as high-pressure homogenization have demonstrated scalability, standardized manufacturing protocols and quality-control frameworks remain insufficiently established [11, 12].

In light of these challenges, there is a clear need for a focused and up-to-date review that not only summarizes recent advances in SLN formulation and applications but also critically examines the translational barriers limiting their clinical adoption. Therefore, the purpose of this article is to comprehensively review the composition, preparation methods, characterization techniques, and pharmaceutical applications of solid lipid nanoparticles, while explicitly identifying current knowledge gaps and future directions related to formulation optimization, scale-up, and clinical translation. By addressing both technological progress and unresolved challenges, this review aims to provide a practical and scientifically grounded resource for researchers and formulation scientists working toward the development of clinically viable SLN-based drug delivery systems.

2. Composition of SLNs

The major ingredients include solid lipids, which serve as the structural backbone of the nanoparticles. Examples of these solid lipids are glyceryl behenate (known commercially as Compritol® 888 ATO), glyceryl palmitostearate (marketed as Precirol® ATO 5), as well as common lipids like stearic acid, cetyl palmitate, and tripalmitin [13]. In addition to solid lipids, surfactants and co-surfactants play a critical role in stabilizing the dispersion of nanoparticles. Widely used surfactants include Poloxamer 188, Tween 80, Span 80, lecithin, and sodium cholate, all of which help to reduce surface tension and prevent aggregation. Finally, the aqueous phase, serves as the dispersion medium, facilitating the overall formulation and stability of the SLNs. Together, these components work synergistically to enhance the delivery and bioavailability of encapsulated active substances [14].

3. METHODS OF PREPARATION

SNLs were prepared by the following techniques:

3.1 High-Pressure Homogenization (HPH)

One of the most common and scalable techniques. The lipid phase containing the drug is melted and mixed with an aqueous surfactant phase, then homogenized under high pressure to form nanoparticles.

Elevated temperatures beyond the lipid's melting point are chosen for this method and can later be regarded as the homogenization process employing emulsifiers. A high shear mixing device is utilized resulting in an oil-in-water type emulsion. The mixture is then allowed to cool, initiating the crystallization of lipids, which leads to the formation of SLNs. To achieve optimal SLN production, 3 to 5 cycles of homogenization at elevated pressures are demanded. It’s important to note that high-pressure homogenization (HPH) causes a temperature increase. As the frequence of cycles or pressure increases, there is an increase in particle size, which occurs due to the attractive forces stemming from kinetic energy. then, the nanoemulsion is cooled prompting the recrystallization of lipids and resulting in the formation of nanoparticles [15].

Cold homogenization is a technique designed to address the issues associated with hot homogenization, such as rapid degradation from high temperatures, loss of drug during the process, and unpredictable changes in the lipid's polymorphic form due to the complexities involved in crystallization. The initial step of the process—dissolving the drug in the lipid melt—remains the same as in hot homogenization. However, subsequent steps differ significantly. The drug-lipid mixture is quickly cooled to ensure an even distribution of the drug within the lipid matrix. After cooling, the mixture is finely ground using a ball mill, resulting in particles that typically range from 50 to 100 µm in size. It is important to note that cold homogenization typically yields larger particle sizes compared to the hot method [16].

3.2 Solvent Evaporation

In this technique, the lipophilic materials and hydrophobic drug are dissolved in organic solvents that do not mix with water, such as cyclohexane. Then, the mixture is emulsified in an aqueous phase employing high-speed homogenization. The coarse emulsion is then promptly passed through a microfluidizer. A rotary evaporator with functioned at room temperature and reduced pressure, is employed to evaporate the organic solvent [16].

3.3 Microemulsion Technique

A microemulsion is assembled by fusing a medicine liquefied in molten lipids with an aqueous phase that comprises emulsifier, all heated then introduced into cold water at temperatures ranging from 2 to 10 °C while being stirred, which leads to the formation of lipid nanostructures that crystallize [17]. This technique was used to create nanostructured lipid carriers (NLCs) employinga phagocytic role to target oligonucleotides within atherosclerosis. This showcases an effective and favorably selective formulation for atherosclerosis therapy. The method is reproducible appropriate for thermolabile drugs. Nevertheless, it necessitates a significant quantity of surfactant and requires the evaporation of excess water after the preparation is complete [1].

3.4 Solvent Injection Method

In this approach, a miscible solvent is utilized to solubilize both the lipid and the medicine, and the aqueous phase mixed with an emulsifier. The lyophilic phase is introduced into the aqueous phase via a needle, creating smaller droplets, which increases the concentration of lipids. These emulsifiers help lessen the interfacial tension, facilitating the creation of tiny solvent droplets that contain lipids. The quick speed at which the solvent is injected drives these droplets to fragment into even more undersized droplets. The energy liberated during the solvent’s redistribution provides the essential energy required for lipid precipitation [19].

3.5 Ultrasonication or High-Shear Homogenization

SLN was also assembled by high-speed stirring or sonication. The gear utilized for this procedure is prevailing. The foremost weakness of this technique is a broader particle size distribution, which is the leading reason for physical instability. Particle gain on storage is an acute problem in this approach. After multiple investigations, it was proven that high-speed stirring and ultrasonication, when utilized combinedly at elevated temperatures, generate a unchanging formula [20].

4. Characterization and Evaluation of SLNs [21].

4.1 Particle Size and Zeta Potential

Measured by Dynamic Light Scattering. Particle size affects drug release and bio-distribution, while zeta potential indicates surface charge and colloidal stability.

4.2 Drug Loading and Entrapment Efficiency

Determined by separating free drug from nanoparticles (via ultracentrifugation or filtration) and quantifying using HPLC or UV spectroscopy.

4.3 Morphological Studies

Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) are employed to study particle shape and surface characteristics.

4.4 Crystallinity and Polymorphism

Differential Scanning Calorimetry (DSC) and X-Ray Diffraction (XRD) assess the crystalline nature of lipids and potential drug–lipid interactions.

4.5 In Vitro Drug Release

Usually performed employing diffusion methods in suitable media. The release pattern (burst, sustained, or biphasic) depends on lipid composition and drug localization.

4.6 Stability Studies

Assessed under various temperature and humidity conditions to evaluate aggregation, polymorphic transitions, and drug degradation over time.

4.7 Sterility and Toxicity Testing

Essential for parenteral applications. Cytotoxicity is tested using cell lines such as Caco-2 or HepG2.

The composition and evaluation parameters of SNP are demonstrated in Figure 1 and table 1.

Figure 1: The composition, preparation and evaluation

Table 1: The evaluation parameters of SNP

5. Applications of SLNs

5.1 Oral Delivery

After being taken orally, drug-loaded solid lipid nanoparticles penetrate the bloodstream via miscellaneous mechanisms, including lymphatic absorption, transport, and endocytosis. Furthermore, SLNs can be coated with distinct polymers (such as chitosan) to enhance their mucoadhesion and increase drug absorption. Numerous studies revealed that SLNs significantly enhance absorption, and oral bioavailability [22].

5.2. Parenteral Delivery

After injection, solid lipid nanoparticles (SLNs) can enhance bioavailability. For instance, SLNs comprising 5-fluorouracil enhanced bioavailability, when administered via the intraperitoneal route, compared to free 5-fluorouracil. These SLNs exhibited more profitable tumor growth inhibition subcutaneously corresponded to the free form of 5-fluorouracil. Ondansetron-loaded SLNs demonstrated sustained-release properties in rats following subcutaneous administration. In a separate study focused on resveratrol-loaded SLNs, the formulation enhanced the cellular uptake of resveratrol, revealing improved efficacy in treating breast cancer compared to free resveratrol [23].

5.3. Transdermal Delivery

SLNs effectively facilitate the transdermal penetration of drugs. They are regarded as safe for physiological use and can help to hydrate the skin. Various studies have performed evaluations of SLNs or SLN gels through in vitro or in vivo methods. For instance, SLNs loaded with tacrolimus achieved skin permeation levels of 25–40%, although the SLN gel resulted in a decrease in skin permeation. Nevertheless, SLN gels enhance drug retention in the skin, making them appropriate for the cure of atopic dermatitis. In a prior investigation, quercetin and resveratrol were co-encapsulated in SLN gel to enhance drug distribution within the epidermis, revealing improved release from the SLN gel effectively than from a standard gel, signifying its potential for skin cancer treatment. In a similar investigation, SLNs that contained isotretinoin exhibited prolonged drug release over 24 hours and notable anti-acne effects. Additionally, a thermosensitive SLN gel loaded with tacrolimus demonstrated deeper skin penetration than a reference product [24].

5.4. Intranasal Delivery

SLNs possess the capability to deliver medications directly to the brain, improving their bioavailability in that area. This enhancement is due to better drug solubility, permeation, and stability. A gel formulation containing both levofloxacin and doxycycline loaded into SLNs exhibited superior brain targeting when compared to pure drug as evidenced by efficiency exceeding 100% [25].

Figure 2: Application of SNP

6. Future Prospects

The future of SLNs in drug delivery retains great potential, particularly as advancements in nanotechnology and pharmaceutical sciences enhance their design and usage. Nevertheless, numerous challenges persist in scaling up SLN production. These challenges encompass inconsistencies between batches, cost-effective manufacturing processes, and the complexities involved in formulation. To address the expenses linked to these innovative delivery systems, researchers are investigating more streamlined approaches for creating SLNs. This involves utilizing standardized, scalable, and efficient development techniques that leverage readily available and affordable materials. Innovations in HPH, solvent emulsification, and microemulsion methods are being refined to boost production efficiency while maintaining the quality and stability of the SLNs [26].

7. CONCLUSION

SLNs have emerged as a versatile and promising nanocarrier system capable of addressing long-standing challenges in drug delivery, particularly for poorly water-soluble and unstable therapeutic agents. Their unique features such as the use of physiologically acceptable lipids, the ability to protect encapsulated drugs, controlled release behavior, and compatibility with multiple administration routes have positioned them as an attractive alternative to conventional delivery systems, including polymeric nanoparticles and liposomes. Extensive research has demonstrated their potential in improving drug solubility, bioavailability, targeting efficiency, and therapeutic outcomes across diverse treatment areas.

Despite these advantages, the successful translation of SLNs from laboratory to industrial and clinical settings is hindered by key formulation and manufacturing challenges. Issues such as polymorphic transitions, limited drug loading, particle aggregation, sterilization difficulties, and batch-to-batch variability remain significant obstacles. Moreover, the scale-up of SLN production requires robust optimization of processing parameters, stabilization strategies, and quality-control measures to ensure reproducibility and cost-effectiveness. Innovations in high-pressure homogenization, solvent based methods, microemulsion techniques, and continuous manufacturing show promise in overcoming these barriers.

The future of SLNs is bright, with ongoing advancements in nanotechnology, surface modification, and targeted delivery opening new avenues for precision medicine. The integration of SLNs with biodegradable polymers, ligands for active targeting, and stimuli-responsive materials may further enhance their therapeutic potential. As research progresses toward more stable, scalable, and patient-friendly formulations, SLNs are expected to play an increasingly influential role in improving drug delivery and shaping the next generation of pharmaceutical technologies.

REFERENCES

1. Kalpana Singh, Shiwani Singhal, Shilpa Pahwa, Vandana Arora Sethi, Shashank Sharma, Preeti Singh, R.D. Kale, S. Wazed Ali, Suresh Sagadevan, Nanomedicine and drug delivery: A comprehensive review of applications and challenges, Nano-Structures & Nano-Objects, Volume 40, 024,101403,https://doi.org/10.1016/j.nanoso.2024.101403.
2. Tarun Sahu, Yashwant Kumar Ratre, Sushma Chauhan, L.V.K.S. Bhaskar, Maya P. Nair, Henu Kumar Verma, Nanotechnology based drug delivery system: Current strategies and emerging therapeutic potential for medical science, Journal of Drug Delivery Science and Technology, Volume 63,2021,102487, https://doi.org/10.1016/j.jddst.2021.102487.
3. Mushfiq Akanda, MD Sadeque Hossain Mithu, Dennis Douroumis, Solid lipid nanoparticles: An effective lipid-based technology for cancer treatment, Journal of Drug Delivery Science and Technology, Volume 86,2023,104709,https://doi.org/10.1016/j.jddst.2023.104709.
4. Tang, C.-H., Chen, H.-L., & Dong, J.-R. (2023). Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) as Food-Grade Nanovehicles for Hydrophobic Nutraceuticals or Bioactives. Applied Sciences, 13(3), 1726. https://doi.org/10.3390/app13031726
5. Ameya Deshpande, Majrad Mohamed, Saloni B. Daftardar, Meghavi Patel, Sai H.S. Boddu, Jerry Nesamony, Chapter 12 - Solid Lipid Nanoparticles in Drug Delivery: Opportunities and Challenges, Editor(s): Ashim K. Mitra, Kishore Cholkar, Abhirup Mandal, In Micro and Nano Technologies, Emerging Nanotechnologies for Diagnostics, Drug Delivery and Medical Devices,Elsevier,2017,Pages 291-330, https://doi.org/10.1016/B978-0-323-42978-8.00012-7
6. Bukke, S.P.N., Venkatesh, C., Bandenahalli Rajanna, S. et al.Solid lipid nanocarriers for drug delivery: design innovations and characterization strategies—a comprehensive review. Discov Appl Sci 6, 279 (2024). https://doi.org/10.1007/s42452-024-05897-z
7. Jyotiraditya Mall, Nazish Naseem, Md Faheem Haider, Md Azizur Rahman, Sara Khan, Sana Naaz Siddiqui, Nanostructured lipid carriers as a drug delivery system: A comprehensive review with therapeutic applications, Intelligent Pharmacy, Volume 3, Issue 4,2025,Pages 243-255,https://doi.org/10.1016/j.ipha.2024.09.005
8. Zhuo, Y., Zhao, Y.-G., & Zhang, Y. (2024). Enhancing Drug Solubility, Bioavailability, and Targeted Therapeutic Applications through Magnetic Nanoparticles. Molecules, 29(20), 4854. https://doi.org/10.3390/molecules2920485
9. Sivadasan, D., Ramakrishnan, K., Mahendran, J., Ranganathan, H., Karuppaiah, A., & Rahman, H. (2023). Solid Lipid Nanoparticles: Applications and Prospects in Cancer Treatment. International Journal of Molecular Sciences, 24(7), 6199. https://doi.org/10.3390/ijms24076199
10. Chaudhary, S.A.; Patel, D.M.; Patel, J.K.; Patel, D.H. Solvent Emulsification Evaporation and Solvent Emulsification Diffusion Techniques for Nanoparticles. In Emerging Technologies for Nanoparticle Manufacturing; Patel, J.K., Pathak, Y.V., Eds.; Springer International Publishing: Cham, Switzerland, 2021; pp. 287–300.
11. Scioli Montoto S, Muraca G, Ruiz ME. Solid Lipid Nanoparticles for Drug Delivery: Pharmacological and Biopharmaceutical Aspects. Front Mol Biosci. 2020 Oct 30; 7:587997. doi: 10.3389/fmolb.2020.587997. PMID: 33195435; PMCID: PMC7662460.
12. Akbari, J., Saeedi, M., Ahmadi, F., Hashemi, S. M. H., Babaei, A., Yaddollahi, S., Rostamkalaei, S. S., Asare-Addo, K., & Nokhodchi, A. (2022). Solid lipid nanoparticles and nanostructured lipid carriers: a review of the methods of manufacture and routes of administration. Pharmaceutical development and technology, 27(5), 525–544. https://doi.org/10.1080/10837450.2022.2084554
13. Patra, C.N., Sahu, K., Singha, R. et al.Multifaceted Applications of Solid Lipid: A Comprehensive Review. Biomedical Materials & Devices 2, 834–860 (2024). https://doi.org/10.1007/s44174-023-00153-1
14. Kaur, J. et al.(2024). Overview of Surfactants, Properties, Types, and Role in Chemistry. In: Manjunatha, J.G. (eds) Advances in Surfactant Biosensor and Sensor Technologies. Springer, Cham. https://doi.org/10.1007/978-3-031-60832-2_1
15. Akanksha G, Deepti S, Navneet G. Solid lipid nanoparticles method, characterization and applications. Int Curr Pharm J, 2012; 1:384 93.
16. Sastri KT, Radha GV, Pidikiti S, Vajjhala P. Solid lipid nanoparticles: Preparation techniques, their characterization, and an update on recent studies. J Appl Pharm Sci, 2020; 10(06):126–
17. Xu, L.; Wang, X.; Liu, Y.; Yang, G.; Falconer, R.G.; Zhao, C.-X. Lipid Nanoparticles for Drug Delivery.  NanoBiomed Res.2022, 2, 2100109.
18. Colaco, V.; Roy, A.A.; Naik, G.A.R.R.; Mondal, A.; Mutalik, S.; Dhas, N. Advancement in lipid-based nanocomposites for theranostic applications in lung carcinoma treatment. Open Nano2023, 15, 100199.
19. Kimura, N.; Maeki, M.; Sato, Y.; Ishida, A.; Tani, H.; Harashima, H.; Tokeshi, M. Development of a Post-Treatment Process Based on Microfluidics for Lipid Nanoparti-cles with Controlled Size and Application in siRNA Delivery. ACS Appl. Mater. Interfaces2020, 12, 34011–34020.
20. Nguyen, T.-T.-L., & Duong, V.-A. (2022). Solid Lipid Nanoparticles. Encyclopedia, 2(2), 952-973. https://doi.org/10.3390/encyclopedia2020063
21. Shabnam Dolatabadi, Maryam Karimi, Samira Nasirizadeh, Mahdi Hatamipour, Shiva Golmohammadzadeh, Mahmoud Reza Jaafari, Preparation, characterization and in vivo pharmacokinetic evaluation of curcuminoids-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs),Journal of Drug Delivery Science and Technology, Volume 62,2021,102352, https://doi.org/10.1016/j.jddst.2021.102352.
22. Pandey S, Shaikh F, Gupta A, Tripathi P, Yadav JS. A Recent Update: Solid Lipid Nanoparticles for Effective Drug Delivery. Adv Pharm Bull. 2022 Jan;12(1):17-33. doi: 10.34172/apb.2022.007. Epub 2021 May 16. PMID: 35517874; PMCID: PMC9012924.
23. Kimberley Elbrink, Sofie Van Hees, Ronnie Chamanza, Dirk Roelant, Tine Loomans, René Holm, Filip Kiekens, Application of solid lipid nanoparticles as a long-term drug delivery platform for intramuscular and subcutaneous administration: In vitro and in vivo evaluation, European Journal of Pharmaceutics and Biopharmaceutics, Volume 163,2021,Pages 158-170,https://doi.org/10.1016/j.ejpb.2021.04.004.
24. Nikhil Kumar, Sujit Kakade, Solid Lipid Nanoparticles; A Comprehensive Review of Preparation, Drying Techniques and Applications, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 4, 3165-3181 https://doi.org/10.5281/zenodo.15285779
25. María L. Formica, Daniel A. Real, Matías L. Picchio, Elise Catlin, Ryan F. Donnelly, Alejandro J. Paredes, On a highway to the brain: A review on nose-to-brain drug delivery using nanoparticles, Applied Materials Today, Volume 29,2022,101631, https://doi.org/10.1016/j.apmt.2022.101631.
26. M NK, S S, P SR, Narayanasamy D. The Science of Solid Lipid Nanoparticles: From Fundamentals to Applications. Cureus. 2024 Sep 6;16(9):e68807. doi: 10.7759/cureus.68807. PMID: 39376878; PMCID: PMC11456405.