Solid Lipid Nanoparticle Preparation Techniques: Comparison
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Solid lipid nanoparticles (SLNs) are an alternate carrier system to liposomes, polymeric nanoparticles, and inorganic carriers. SLNs have attracted increasing attention for delivering drugs, nucleic acids, proteins, peptides, nutraceuticals, and cosmetics. These nanocarriers have attracted industrial attention due to their ease of preparation, physicochemical stability, and scalability. These characteristics make SLNs attractive for manufacture on a large scale. 

  • solid lipid nanoparticles
  • drug delivery
  • nanomedicines

1. Ultrasonication

Ultrasonication is a dispersing technique that was first used to create stable lipid nanodispersions. Ultrasonication operates by dispersing molten lipids into minute droplets in a continuous phase. This method creates SLNs without using organic solvents and is fast, simple, and efficient. However, it has the disadvantage of necessitating an additional filtration step of the formulated SLN emulsion to eliminate impurities such as metal generated by ultrasonication, and it is frequently hindered by the occurrence of microparticles [5][1]. The idea behind this technique is to use sound waves to reduce particle size [17][2].
Two methods of sonication are generally used depending on whether a probe tip ultrasonic disintegrator or a bath is used. While the bath sonicator is preferable for large volumes of diluted lipid dispersions, the probe sonicator is well suited for dispersions that require a large amount of energy in a low volume. Probe tip sonicators provide large energy to lipid dispersions; however, they can also induce lipid degradation due to overheating. Metal particles are often released by sonication tips into the dispersion, which should be removed by centrifugation before use. Bath sonicators are favored compared to probe tip sonicators for these reasons. The composition and concentration of lipids, duration, power, and temperature used for sonication all affect lipid dispersion particle size and size distribution [20][3].
The equipment used in this process is widely available at lab size, which is an advantage. This method, however, has drawbacks, such as a broader size distribution that extends into the micrometer range. Other disadvantages of this method include potential metal contamination and physical instability, such as particle growth when stored [21][4]. To control the size of nanoparticles, the frequency and strength of ultrasonication can be adjusted. Various research groups have attempted to prepare a robust solution by combining high-speed stirring with ultrasonication procedures carried out at elevated temperatures [22][5].
The probe ultrasonication technique was used by Bose et al. to produce quercetin SLN [25][6]. V. Venkateswarlu and K. Manjunath developed clozapine-loaded SLNs using hot homogenization followed by ultrasonication at a temperature greater than the melting point of lipids, and the results indicated that more than 90% of the drug was entrapped in SLN [26][7].
It is essential to investigate the SLN stability under various conditions, however several researchers ignore this important aspect. In a detailed investigation, DA Campos and coworkers studied phenolic compound rosmarinic acid (RA)-encapsulated SLNs prepared by the hot melt ultrasonication method. It was observed that the liquid state SLNs were stable for 90 days and the freeze-dried SLNs were stable up to 1 year [27][8]. These studies indicate that SLNs are suitable for herbal medicine delivery [28,29][9][10].

2. Solvent Emulsification Evaporation

Solvent emulsification evaporation is a dispersion technique to produce SLNs, which is a suitable method for thermolabile drugs such as ritonavir, chloramphenicol, and cyclopentolate. Here, the lipophilic drug and the lipid are dissolved in an organic solvent and thoroughly mixed to produce a homogeneous transparent lipid solution that is immiscible in water. Once the organic phase is prepared, it is emulsified with the appropriate amount of water (aqueous phase) using a high-speed homogenizer, giving us a coarse emulsion (o/w emulsion). This o/w emulsion is converted into a nanoemulsion with the use of a high-pressure homogenizer that breaks down globules into particles. To extract and eliminate the remnants of organic solvent, the nanoemulsion was kept in a hood or on a magnetic stirrer overnight with constant stirring. After the organic solvent evaporates, the lipid content precipitates in the bath, forming nanodispersion. Filtration by sintered disc filter funnels separates the precipitation of lipids in aqueous media. This method produces nanoparticles that are nonflocculated (single entity) with good entrapment quality [30][11]. Now, factors such as the type and amount of lipid, surfactant, and cosurfactant present in the organic phase are crucial in determining the particle size of the nanoparticles. For example, if we use a lipid content up to 5% by weight, it produces particles of size 30–100 nm. However, as the lipid content increases, the particle size also increases, perhaps due to the high viscosity of the dispersed phase causing a drop in homogenization efficiency [22][5]. This method produces nanoparticles that are compact and have a high encapsulation performance. The procedure can be optimized and expanded to produce large volumes of nanoparticles [31][12].

3. Solvent Emulsification-Diffusion

This is a modified and better version of the previously mentioned “solvent emulsification evaporation” process. Unlike the process described above, the solvent used in the solvent emulsification diffusion procedure is partly miscible with water, has lower toxicity and can be executed in both an aqueous and an oil form (for example, benzyl alcohol, butyl lactate, isopropyl acetate, methyl acetate, isovaleric acid and tetrahydrofuran). Thermodynamic equilibrium is maintained by saturating organic solvents with water. The basic mechanism of this technique is lipid crystallization caused by solvent migration from the internal organic phase to the external aqueous phase [31][12].
Nanoparticles with particle sizes of 100 nm and below can be obtained by this technique, in which surfactants play a vital role in optimizing the size. Similar to the previously described process, a drug dissolved in the organic solvent immediately precipitates out due to the diffusion of the organic solvent [22][5]. The lipid and drug are dissolved in a water-saturated solvent (internal phase) and emulsified using a mechanical stirrer with the dispersed phase (aqueous solution containing stabilizer). Water is added to the system after the o/w emulsion is formed to facilitate solvent diffusion into the continuous process, resulting in lipid precipitation in nanoparticulate form. This approach is effective and adaptable, has easy implementation and scaling-up properties, low physical tension (i.e., short exposure to elevated temperatures and mechanical dispersion) and eliminates the requirement of dissolving the drug in the melting lipid. The necessity to purify and concentrate the SLN dispersion and drug permeation into the aqueous process occurs quickly, resulting in low drug entrapment in SLN, which are both disadvantages of this approach [20][3].

4. Membrane Contactor

Due to its excellent scaling-up ability, the membrane contact technique is highly suitable for producing lipid nanoparticles on a large scale. It uses a simple apparatus to prepare solid lipid nanoparticles, and if the conditions are made favorable by careful selection of process parameters such as temperature or pressure, the particle size can be controlled, which makes the process more advantageous [22][5]. In this process, we have a lipid phase containing drug and an aqueous phase containing surfactant. The lipid phase is melted beyond its melting point and permeated through a porous membrane under pressure, which allows the formation of nanosized droplets. The aqueous phase keeps flowing tangentially in the internal membrane module, which sweeps away particles formed at the pore outlet of the membrane. The aqueous phase is retained at the lipid melting temperature. The formation of SLNs takes place when this preparation is solidified by cooling to room temperature or by keeping this preparation in a thermostatic bath of the desired temperature [31][12]. The particle size of lipid nanoparticles is influenced by many criteria, such as lipid phase temperature, pressure, aqueous phase temperature and cross-flow velocity, and membrane pore size [32][13].
Charcosset and coworkers experimented to learn the effects of different process parameters on the particle size of lipid nanoparticles where vitamin E-loaded SLNs were prepared using the membrane contractor technique [33][14]. They observed that there was an increase in lipid phase flux with a rise in the lipid phase pressure, so at the highest pressure, there was a slight decrease in particle size. Another interesting observation they found was that below the temperature of the lipid fusion point, the flux time increased, but smaller particles were formed. However, above the fusion point, the flux time decreased, and the particle size increased [5][1].

5. Double Emulsification

For the preparation of SLNs, APIs (active pharmaceutical ingredients) and hydrophilic proteins and peptides are acceptable [34][15]. A W/O emulsion is created in this process by mixing an aqueous solution consisting of medication with a mixture of melted oily phases at a temperature just above the melting point to obtain a clear solution. Excipients are used to stabilize the primary W/O emulsion, which is dispersed to the aqueous phase, cosurfactant, and surfactant to obtain a clear double W/O/W emulsion system. The warm double emulsion is then dispersed with cold and rinsed with a dispersion medium, resulting in the creation of SLNs [31][12].
Some of the disadvantages of the double emulsion method for SLN preparation are instabilities due to the coalescence of aqueous droplets inside the oily phase, rupturing of the coating on the surface of the interior droplets, and agglomeration of the oil droplets [36][16]. Trehalose is a disaccharide and is used as the most effective cryoprotectant in drying (specifically in the case of freeze-drying). This favors the preservation of the colloidal particle size of SLN formulations after reconstitution. For SLN preparations, a concentration of 1% SLN in trehalose (in water) or 20% trehalose (in ethanol-water mixture) yields the desirable results after drying of SLN.

6. Supercritical Fluid Extraction

This is one of the most promising methods for producing solid nanoparticles, which works on the basic principle that lipid nanoparticles are formed from o/w emulsions by supercritical fluid extraction (SCF) [9][17]. The main advantage of this approach over other techniques is that it uses low temperatures (35 °C) and does not use organic solvents to make nanoparticles, i.e., solventless processing [37][18]. Carbon dioxide (CO2) is often used as SCF with or without the addition of other solvents. The particles obtained from this process have smaller particle sizes and distributions, have smooth surfaces and are free flowing, which justifies the advantages of this method. However, there are drawbacks to this approach, such as the cost, CO2’s low solvent strength, and the need for large volumes of CO2. SCF can be used as a solvent, swelling and plasticizing agent, antisolvent, or solvent for polymerization in dispersed media in nanoparticle processing [22][5]. The rapid expansion of supercritical CO2 solutions will generate SLNs [22][5]. CO2 with a purity of 99.99% is an excellent solvent for preparing SLNs using this form [32][13]. Gas-saturated solutions (GSS), such as ammonia, chlorodifluoromethane (CHClF2), 1,1,1,2-tetrafluoroethane (CH2FCF3) and ethane, are the best SCF [20][3] and aid in the melting of lipid materials, which then dissolve in the SCF under pressure with the lipid melt and GSS [38][19]. Spraying the saturated solution via the atomizer or nozzle causes it to expand and quickly release SCF, leaving fine dry lipid particles behind [30][11].
“Supercritical fluid extraction of emulsions (SFEE)” is the term used to describe the method of creating lipid nanoparticles using emulsions through SCF technology. The lipid component and the drug are dissolved in an appropriate surfactant-containing organic solvent, such as chloroform, to produce the organic phase. A high-pressure homogenizer is used to combine the organic solution with an aqueous solution that may additionally have a cosurfactant to create an o/w emulsion. The supercritical fluid (kept at fixed temperature and pressure) is currently supplied counter, while the o/w emulsion is delivered from one endpoint of the extraction unit (typically the top) at a fixed flow rate. Continuous solvent extraction from o/w emulsions is being used to form lipid nanoparticle dispersions [31][12].

7. Spray Drying Method

Spray drying is the method used to create solid preparations from solutions and suspensions. The conversion of lipid nanoparticles from aqueous dispersion into a dry powder is very helpful for enhancing stability. Spray drying can change aqueous dispersions into a dry, fine, reconstituted powder that can be kept for a prolonged period [40][20]. Spray-drying is commonly used in the pharmaceutical industry. Spray drying is a one-step procedure for converting liquid feed to a dried atomized state. The feed is usually in the form of a solution; however, it can range from coarse to fine suspensions. The feed is first converted into spray form via different atomization methods, such as centrifugal, ultrasonic, or electrostatic atomization, which then is instantly put in contact with thermal hot gas, which leads to rapid solvent evaporation into a dried solid form. A cyclone separator, an electrostatic precipitator, separates hot air from dried solid particles. The capacity to control process parameters is the primary benefit of spray drying and it has specializations to manipulate a variety of parameters, such as feed composition, temperature, relative humidity, drying rate, and gas flow rate. As a result, spray drying technology permits the adjustment of particle characteristics, namely, size, size distribution, shape, density, and morphology, as well as macroscopic powder qualities, such as bulk density, tap density, powder flowability, and dispersibility. Physicochemical instability, which includes particle growth, unanticipated gelation, drug expulsion upon storage, or unexpected dynamic polymorphic changes of the lipid particles, is the main drawback of SLNs [41,42][21][22].

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