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SMEDDS SEDDS SNEDDS 1. Size <250 nm >300 nm <100 nm 2. Appearance Optically clear Turbid Optically clear 3. Hydrophilic–lipophilic balance (HLB) value >12 <12 >12 4. Classification of lipid-based drug delivery system Type IIIB Type II Type IIIB 5. Concentration of oil >20% 40-80% >20% 6. Concentration of surfactant 40-80% 30-40% 40-80% 7. Material Oil, surfactant, and co-solvents (both water soluble and insoluble excipients) Oil water insoluble surfactant Oils without surfactants (e.g., tri-, di-, and monoglycerides) 8. Characteristics SMEDDS create with aqueous soluble elements SEDDS create without aqueous soluble elements Nondispersing requires digestion 9. Advantages Clear dispersion, absorption of drug without digestion Improbable loss of solvent, capacity on dispersion Good solvent capacity for many drug formulations. 10. Disadvantages Less easily digested Turbid o/w dispersion Poor solvent capacity until drug is lipophilic

      Cubosomes and hexosomes have generated great attention as they are the first to have molecular, multilevel, mesophasic, and nanoparticle observed structural compounds. They can be administrated through various routes thus providing versatility in the administration of various drugs. Internal structure defined before dispersion by liquid crystal mesophases of amphiphiles offers complex topologies; they can carry a higher volume of drug with long-term release [75]. Size ranges vary in the nanometer range, which allows similar surfactant to uniformly distribute and prevent aggregation. Since it possesses the curvature in the internal structure of crystalline mesophases, large volume of the drug can be loaded, which increases the potential for drug targeting [76, 77]. Due to the amphiphilic nature of liquid crystal forming lipid (polar head and lipophilic tail), they arrange themselves into a cubic or hexagonal phase, which is thermodynamically stable. Therapeutic applications of liquid crystal nanoparticles (cubosomes and hexagonal) are associated with the drug, route of delivery, formulation, and physiochemical properties such as increased molecular weight, the different polarity of drug molecule, compatibility issue, enzymatic degradation, and reduced toxicity.

1.4 Methods of Preparation of Lipid Nanocarriers

There are various high energy input and low energy input methods available for the preparation of lipid-based nanocarriers. The methods presented here include physical ones like homogenization and chemical ones like co-acervation. The choice of methods and energy input depends on the thermal stability of lipid molecules as well as drug molecule. Several important methods utilized for the preparation of lipid nanocarriers are given in Table 1.3.

1.5 Challenges and Hurdles

      1.5.1 Scale Up and Stability Issues

The development of the lipid-based nanocarrier system can easily be scaled using the reported approach for preparation. Several issues of stability can, however, be associated with lipid carriers and can be a hurdle in the process of the scale-up. Polymorphism must first be taken into account. The colloidal size and particularly their high volume-to-surface ratio can result in the decrease in melting points. This effect may also be caused by impurities, agents, and stabilizers [86, 87]. For example, the co-acervation and hot homogenization method of fatty acids and triglycerides results in polymorphism [88]. Due to rapid solvent evaporation, polymorphic forms have been obtained during spray drying.

Table 1.3 Different types of techniques used in the preparation of lipid nanocarriers.

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Preparation techniques	Description		References
High-pressure homogenizationPressure: 100–2000 bar	Hot homogenization	Drug melted in hot lipid Pressure: 500–1500 bar Production of nanoemulsion	[78, 79]
	Cold homogenization	Suitable for thermosensitive drug.Formulation rapidly cooled in dry ice.
Ultrasonication	Probe ultrasonication	Use for oral drug delivery systems.Diameter range: 80–800 nmReduce shear stress.	[80]
	Bath ultrasonication
Solvent emulsification–diffusion method	Lipid dissolved in organic solvents (chloroform, ethyl acetate, methylene chloride, cyclohexane).Use for hydrophilic drug (w/o/w emulsion).Diameter range: 30–100 nm.		[81]
Supercritical fluid method	Lipophilic substances dissolved in organic solvent.Nanoparticle range 25 nm.Solvent removal by evaporation (pressure 40–60 mbar).		[82]
Microemulsion-based method	Two-phase system inner and outer (o/w microemulsion)Lower mechanical energy.Increased drug loading capacity, range of 200–250 nm.		[82]
Spray drying method