High Energy Approaches

High Pressure Homogenization (HPH) Technique

The method involves the use of high pressure (100-2000 bar) to push the liquid using high-pressure homogenizers. This pressure results in high shear stress in the surface of the liquid, and the cavitation forces induced break down the size of accelerated particles into a sub-micrometer or nanometer range. It is considered to be the most reliable and powerful method for the large-scale production of LNs. This process can be carried out both at an

Pictorial representation elucidating the contrast between SLN and NLC structure (Patel et al., 2013)

FIGURE 4.2 Pictorial representation elucidating the contrast between SLN and NLC structure (Patel et al., 2013).

elevated temperature (hot HPH) as well as below room temperature (cold HPH). Figure 4.3 shows the schematic representation of the hot and cold HPH method. Initially, the lipid matrix containing either a mixture of solid lipid and liquid lipid (in the case of NLCs) or only solid lipid is melted above the melting temperature of the lipid (Bevilacqua et al., 2007). Hot HPH

A coarse pre-emulsion is formed using simple stirring to mix the melted lipid matrix with aqueous surfactant solution. HPH is then applied at an elevated temperature above the characteristic melting point of each lipid to obtain a hot o/w nano-emulsion. Further, the obtained nano-emulsion is cooled down to room temperature or refrigeration conditions to solidify the lipid droplets and formulate LNs. Cold HPH

The major disadvantage linked with the hot HPH method is drug degradation at high temperature. To overcome this limitation, the cold HPH was exploited. This involves the solidification of the premixed API in the melted lipid matrix using liquid nitrogen or dry ice and milling up to micron level. The lipid microparticles are later mixed in an aqueous surfactant solution and subjected to HPH at room temperature to form LNs.

High Speed Homogenization (HSH) or Ultrasonication (US)

Homogenization and ultrasonication are well explored dispersing techniques which can also be employed together in synergy with each other for the fabrication of LNs. The melted lipid matrix (above the melting point of lipid) is dispersed into the aqueous surfactant solution by HSH followed by US.

Further, warm emulsion is cooled down below the crystallization temperature of the lipid and LNs’ dispersion is made (Aditya et al., 2013). The schematic representation of the HSH method followed by US is given in Figure 4.4.

Low Energy Approaches


The micro-emulsification method is the simplest and one of the most explored methods for the formation of LNs of requisite size. It simply involves the mixing of the aqueous surfactant solution (surfactant, co-surfactant, and water) with the lipid matrix under constant stirring to develop a hot microemulsion. Later, this hot mixture is quenched into a high volume of cold water (2-3°C) to solidify the lipid droplets (Kanwar et al., 2016). A schematic illustration of the micro-emulsification technique is represented in Figure 4.5.


Strengths and Weaknesses of the Preparation Methods for SLNs and NLCs






High energy approaches


High-pressure homogenization (HPH)

Promising dispersing technique

Energy intensive process


Ascendible, commercially available

Temperature actuated degradation of the drug and the carrier, co-existence of supercooled melts and crystalline modifications

Cold HPH

No temperature induced drug degradation and crystalline-refinement

High energy input, high polydispersity, large particle size, abrasive homogenization conditions, unsubstantiated scalability


Ultrasonication or High speed homogenization

Low shear stress and small particle size

Metal contamination, energy intensive process, poor entrapment efficiency, physical instability


Low energy approaches



Simple, reproducible, theoretical stability, low energy input, narrow size distribution

Low nanoparticle concentration, sensitivity, labor intensive, high concentration of surfactants/ co-surfactants, high dilution ratio


Phase inversion temperature (PIT) technique

Less energy intensive, no solvent requirement, heat sensitive molecules can be aimed

Unstable emulsion, additional molecules can be assimilated to easily affect the inversion phenomena


Membrane contractor method

Scalable, controllable size

Membrane clogging


Approaches with organic solvents


Solvent emulsification -evaporation technique

Small particle size, effective in case of thermolabile drugs, high encapsulation efficiency, monodispersity, low energy input, low viscous system, avoid heat

Unstable emulsion, low dispersing ability, insolubility of lipids in organic solvents, needs additional solvent removal step


Solvent emulsification-diffusion technique

Evade heat during synthesis, utilizes partially water-miscible solvent

Unstable emulsion, low dispersing ability, insolubility of lipids in organic solvents, demands additional solvent removal step


Solvent injection technique

Easy to handle, demands no special instrument like HPH, small sized particles, increased lipid concentration

Particle size variability


Supercritical fluid method

Dry powder of particles is obtained, evade the use of solvents, require mild temperature and pressure, CO, solution is regarded as a good choice of solvent

Extremely expensive

Phase Inversion Temperature (PIT)

The reversal of phase from o/w to w/o emulsion with change in temperature is called the PIT. To obtain the required LNs, the aqueous and non-aqueous phases are heated together above the PIT. Generally, three heating and cooling cycles are repeated, starting from room temperature to PIT, followed by the final step of dilution with cold water (0°C) (Heurtault et al., 2002). Figure

4.6 showcases a flow diagram of the PIT method.

Double Emulsion Technique

This technique is preferred for the loading of hydrophilic API and peptides in SLNs and NLCs. Firstly, primary w/o emulsion stabilized with suitable excipients is formulated by emulsifying the aqueous drug solution with the melted lipid phase (Figure 4.9). Then, the formed primary w/o emulsion is added to the hydrophilic emulsifier solution, leading to the formation of a double w/o/w emulsion. The latter is then isolated by filtration after the formation of SLNs/NLCs by continuous stirring (Yang et al., 2011). The steps involved in the double emulsion technique are shown in Figure 4.7.

Membrane Contractor Method

This method involves the use of a cylindrical membrane module to synthesize the SLNs/NLCs. The aqueous phase containing an emulsifier is circulated in the internal channel of the membrane, and melted lipid is pressed at the temperature above the melting point of lipid through membrane pores into internal water flow, letting the formation of small droplets which are swept away by the aqueous phase. Later the SLNs/NLCs are formed by cooling down the produced droplets of melted lipid to room temperature (Ahmed El-Harati et al., 2006). Figure 4.8 shows a schematic representation of the membrane contractor method.

Approaches with Organic Solvents

Solvent Emulsification-Evaporation Technique

Lipid is dissolved in a water-immiscible organic solvent with low boiling point (like chloroform, cyclohexane) and emulsified in an aqueous surfactant solution using HSH and the resulting coarse pre-emulsion is passed through HPH to obtain nano-emulsion.

High-pressure homogenization (HPH) technique a) Hot HPH and b) Cold HPH. (Reproduced from Ganesan and Narayanasamy, 2017. Copyright 2020 Elsevier.)

FIGURE 4.3 High-pressure homogenization (HPH) technique a) Hot HPH and b) Cold HPH. (Reproduced from Ganesan and Narayanasamy, 2017. Copyright 2020 Elsevier.)

After the solvent is evaporated using a rotary evaporator at 50-60°C, LNs are formed (Negi et al„ 2014).

Solvent Emulsification-Diffusion Technique

Partially water-miscible solvents such as tetrahydrofuran, benzyl alcohol are employed to dissolve the lipid. Organic solvents are saturated with water for establishing the initial thermodynamic equilibrium between the solvent and water. Next, the organic solvent diffuses from an organic phase to aqueous phase, resulting in the solidification of the dispersed phase and crystallization of the lipid (Trotta et al., 2003).

Solvent Injection Technique

The lipid, dissolved in a water-miscible solvent (like methanol, ethanol, acetone, dimethyl sulfoxide) is injected into an aqueous solution of surfactant using an injection needle. Similar to the solvent emulsification-diffusion method, here, too, lipid crystallization is effected by the diffusion of the organic solvent from the organic phase to the aqueous phase (Schubert and Miiller- Goymann. 2003).

A combined pictorial representation of solvent emulsification- evaporation, solvent emulsification-diffusion, and solvent injection methods is given in Figure 4.9.

Micro-emulsification technique

FIGURE 4.5 Micro-emulsification technique.

Supercritical Fluid (SCF) Method

In this method, the organic phase is prepared by solubilizing the drug and lipid in an organic solvent (such as chloroform) in the presence of an appropriate emulsifier. After dispersing the organic phase into an aqueous emulsifier solution, the formed mixture is successively passed through a HPH to form an o/w emulsion. Later, the o/w emulsion is introduced from one end of the extraction column and the supercritical fluid (maintained in constant physiological conditions) counter-currently (at a constant flow rate) from another end.

SLNs/NLCs dispersions are prepared by continuous extraction of the solvent from the o/w emulsions (Chattopadhyay et al., 2007). The schematic representation of supercritical fluid (SCF) is shown in Figure 4.10.

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