Table 2.

List depicting various solid lipid nanoparticles preparation methods, procedures, advantages, and limitations.

Method	Procedure	Mechanism	Advantages	Limitations	Reference
High-pressure homogenization Hot homogenization technique	The temperature of solid lipids is kept above their melting point. At this point, actives can be added. At the same temperature, the molten mixture was added to an aqueous solution with a stabilizing agent. Solution or dispersion subjected to homogenization under high pressure (400–800 bar) resulting in high velocity (27.78 m/s) stream subjected to intensive turbulent physical forces	Submicron particle size is generated by forming high shear forces, cavitation forces, current of eddies, and pressure distortions in the mixture	Useful for thermostable drug, efficient dispersion technique to obtain nano-size range particles (50 nm–400 nm), low risk of product contamination, allows aseptic production of nanoparticles, and easy to scale-up	High polydispersity, the chance of metal contamination, unsuitable for the thermolabile drug due to heat generation during the process, expensive equipment. Coexistence of supercooled melts, various colloidal structures during lipid crystallization, and partitioning of drug towards the aqueous phase	[65,66]
Cold homogenization technique	A melted mixture of lipid is cooled and milled to coarse dispersion having particle size range (50 μm–100 μm). Subsequently distributed in water containing the emulsifying agent and homogenized at room temperature		Feasible for thermolabile drugs; the coexistence of other colloidal structures is minimum	Prerequisite of micronized drug particles in dispersion before homogenization step	[67]
Microemulsion technique	The microemulsion is formed by dispersing molten lipids with an aqueous solution of surfactant and cosurfactant at the same temperature. Hot microemulsion diluted with an excess quantity of cold water at a ratio of 1:25 to 1:100 resulting in the spontaneous formation of SLN	Negative surface free energy contributed by a large reduction of interfacial tension and large changes in the entropy of mixing	Kinetically stable and is a low energy process	Requires a large amount of surfactant and cosurfactant, and highly diluted preparation requires an additional processing step for product concentration	[68]
Supercritical fluid technique	Gas saturated solution containing lipid material. Supercritical fluid containing lipid material and gas saturated solution under pressure is sprayed through nozzle or atomizer under high pressure	Expansion of solution leads to escape of gas and rapid precipitation nanoparticles	Organic solvent-free process, obtain particles as a dry powder, and wide range of miscibility of lipids in gases	Expensive process and equipment	[64]
Solvent emulsification/ evaporation method	The aqueous phase is combined with lipid material that has been dissolved in an organic solvent. The coarse emulsion is nanosized with a high-speed homogenizer and high shear homogenizer. Evaporation of organic solvent leads to precipitation of nanoparticles	Emulsification of globules followed by evaporation of organic solvent leads to precipitation of nanoparticles	Low energy process, uniform size particles <25 nm, and suitable for thermolabile drugs	The insolubility of lipids in organic solvents, thermodynamically unstable, the presence of residual solvent requires additional drying or ultrafiltration procedure, and toxicological consideration	[69]
Solvent emulsification-diffusion method	Lipid dissolved in organic solvent stirred with a partially miscible aqueous solution containing surfactant. Evaporation of organic solvent carried out by high-speed homogenization followed by high shear homogenization	Spontaneous diffusion of hydrophilic solvents resulting in the creation of interfacial turbulence, following the evaporation of the organic solvent, and nanoparticles precipitate	Low polydispersity with an increase in the concentration of hydrophilic solvents, particle size decreases, suitable for thermosensitive drugs	The insolubility of lipids in organic solvents. Thermodynamically unstable. The presence of residual solvent requires freeze-drying or ultrafiltration techniques. Toxicological issue	[70]
Double emulsion	Water-in-oil (w/o) emulsion containing lipophilic surfactant is dispersed in an aqueous phase with a hydrophilic surfactant to formulate water-in-oil water (w/o/w) multiple emulsions. Nanoparticles are formed by continuous stirring and the evaporation of the solvent	Evaporation of solvent from thermodynamically unstable multiple emulsion leads to solidification of emulsion and lipid crystallization	Suitable for hydrophilic and peptide-based drugs, surface modification of nanoparticles is possible by incorporating hydrophilic polymer	Tends to form large particles and the requirement of multiple steps	[71]
Phase inversion temperature	Holding w/o emulsion prepared above a phase-inversion temperature of non-ionic surfactant with continuous stirring and rapidly cooled below the crystallization temperature of the emulsified phase led to the formation of SLNs	During heating, dehydration of ethoxy groups and increased lipophilicity of surfactants. The system crosses a threshold of zero surfactants happens. Spontaneous curvature and minimum surface tension during cooling, favoring the creation of finely dispersed nanoparticles	The low energy emulsification process, requires only a limited quantity of surfactant, capable to produce uniform size nanoparticles, and economical	Low stability and several temperature cycles may be required	[72]
Membrane contractor	Fine droplets are formed when the melted lipid phase is driven through pores of a membrane that is held above melting temperature. Droplets formed at the outlets are swept into an aqueous medium comprising surfactant flows tangentially to the membrane surface and cooled to room temperature, resulting in the production of SLNs	Emulsification of droplets takes place spontaneously at the interfacial surface of the membrane	Changing the flux through the membrane control the particle size, and feasible scale-up process	Many formulation and process parameters are involved, and the membrane prone to clogging	[73]
Solvent injection	To dissolve lipids and medications, a water-miscible solvent or a water-miscible solvent mixture is utilized. Under continuous mechanical agitation, the organic phase is swiftly injected into the aqueous phase containing surfactant or surfactant combination using a needle	Solvent diffusion from lipid to the aqueous medium. Interfacial cavitation and vibration broke down solvent-lipid droplets to a nano-size and lipid sedimentation	Simplicity, clarity, speed of output, and lack of a complicated instrument	Additional step required for residual solvent removal	[39]