LITMIR.BIZ

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Use for lipid with melting point more than 70°C.Alternative technique to lyophilization process. [83] Double emulsion method w/o/w two-step microemulsion technique.Drug is encapsulated with stabilizer to prevent leakage of drug. [82] Precipitation technique Glycerides dissolved in an organic solvent.Solution is emulsified in aqueous phase. [84] Film-ultrasound dispersion Form uniform size nanoparticles.Drug and lipid put in suitable organic solvent. [82, 85]

Furthermore, sterilization is an important stability parameter in lipid nanocarrier system production [89]. Irradiation is an existing technique of sterilization for pharmaceuticals. However, during irradiation, the chemical degradation of the lipids can occur: therefore, ionizing radiation is not allowed, or at least more tests are required before it is accepted as a safe and effective technique of sterilization. Diverse studies have preferred an autoclave approach because it doesn’t change the Zeta potential and mean particle size, although this is paradoxical considering the effect that temperature may influence the stability of nanoparticles.

      Another significant cause for instability is phase separation [88] because of the formation of reversible or irreversible particles (coalescence, sedimentation); also during storage, gelling may occur. Adequate surfactants can be used to address these problems: they can stabilize LNP suspension by an electrostatic repulsion, which improves Zeta potential, or they can serve as steric (non-ionic surfactants) stabilizers. Surface stability, particularly electrostatic stabilization and Zeta potential, is highly sensitive to pH and eventually exists at the external phase, which may cause suspension destabilization.

      The acquisition of solid water forms is an effective strategy for overcoming the problems concerning lipid nanocarrier storage stability. This can be achieved through spray drying or lyophilization of suspension.

      Instability may occur in gastrointestinal fluids following enzymatic degradations of the particles or lipid matrix. Particle accumulation can be accomplished by improving the surfactant combination owing to ionic strength and acidic stomach pH. Stability conditions in combination with steric stabilization have been set at minimum 8–9 mV Zeta Potential [89].

      Lipid nanocarriers have recently been investigated for their interaction with the major circulatory protein serum and albumin. Several groups of researchers also focused more and more on improving their body fluid stability through coating lipid nanocarriers with hydrophilic molecules like poly(ethylene)glycol (PEG) derivatives. Coating lipid nanocarriers with PEG improves stability and plasma half-life to suppress phagocytic uptake, thus improving drug bioavailability [90].

      1.5.2 In Vivo Elimination of Nanocarriers

      In order to deliver several drugs and activities for different objectives, lipid nanocarriers were developed. Still, the in vivo fate of such carriers remains questionable. Although majority of the lipids undergo biotransformation and deemed to be eliminated by common elimination pathways, researchers need to ensure their complete eradication after the drug has been completely released from such carriers. Nonetheless, several obstacles for lipid nanocarriers are still a hot topic for drug therapy among the most interesting and recent assignments for lipid nanocarriers. Cancer treatment, blood-brain barrier (BBB) elimination, and protein and gene delivery are fields of study where a healthy and reliable carrier of drug is essential, and lipid nanocarriers for such purposes are suggested and investigated.

1.6 Characterization Techniques for Lipid Nanocarriers

      1.6.1 Size and Morphology

During parenteral administration, a significant factor in safety of biological systems is the particle size of the carrier system. Dynamic light scattering (DLS) is a method most often used for calculating particle size in solutions and conducting distribution-size study. Quasielastic light scattering or photon correlation spectroscopy (PCS) is the other term used instead of DLS. The method is based on Brownian movement of particle in dispersion. When laser light hits objects, it is scattered by Brown’s particle movement [91]. The motion of the particles depends on the size of the particle. The light intensity of laser light with a defined wavelength fluctuates the particles, which fluctuate the scattered light after striking with dispersed particles. By measuring the frequency of the scattered light fluctuation, the intensity of the Doppler shift can be determined by the use of a photon detector, depending on time and fluctuation. Fluctuations in light intensity are greatly affected by the viscosity of the solution and the temperature; hence, the particle size of dispersion can vary [91, 92–94].

      Scanning electro-microscopy (SEM) and transmission electron microscopy (TEM) are the most needed tools to analyze morphological characteristics [95]. SEM and TEM characterization of nanoparticles provides shapes and surface facets, and it determines the accurate particle size of a particular particle in dispersion [96]. The morphological shape details can be taken from the SEM image for a large nanocrystal with a normal design. SEM works on the basis of scattered electrons and provides particulate morphology. The shape of a small nanocrystal cannot be analyzed by SEM because of its restricted resolution. Although TEM analysis is able to represent the morphology of such particles that are not suitable for SEM by passing electrons through in resultant, it differentiates the chemical entities on the basis of electron density [97].

      Polarized light microscopy (PLM) is usually used to observed lyotropic liquid crystalline structures [98]. It can be used to confirm the presence of liposomes and similar structures in parenteral dispersion systems. The coordinated structure of the phospholipid surfaces results in anisotropical properties. Anisotropic systems deviate polarized light in the plane, which helps in imaging and gives a standard black and white or colored image using a λ-plate [98, 99].

      SEM imaging only analyzes the samples in 2-D, that is, x- and y-axes, but cannot measure the z-axis to provide 3-D morphological information of a particle surface. Atomic force microscopy (AFM) overcomes this problem by analyzing the surface on the z-axis along with the x- and y-axes using deflection of a fine leaf spring. AFM is widely used for crystallinity studies of a sample. The technique uses fixed wavelengths to provide information on the molecular organization of crystals. In AFM imaging, with resolution up to 0.01 nm, the force between the surface of the material and the sensor tip is used [100]. Silicon wafers are usually used for sample fixation. The sample surface should be extra smooth for AFM imaging [101–106].

      1.6.2 Surface Charge

Zeta potential is an essential characteristic of particles that can be easily calculated with a zetasizer tool [92]. It is an important aspect to understand particle stability. In drug delivery applications, the particle charge is an important factor. “Zeta potential is the potential differentiation between the surface and the stationary fluid layer connected to the dispersed sample.” The particle surface is surrounded by ions charged opposite to each other, which generates the thin stern layer adsorbing non-hydrated co-ions and counter ions at the surface. The next layer consists of the hydrated/partially hydrated counter ions, and the last layer consists of co-ions; this layer is known as the diffuse layer. This layer is attached to the slip plane, an imaginary plane that separates mobile ions from immovable ions on the surface. A stable dispersion has zeta potential ideally from -30 to +30 mV. Repulsion occurs between particles with a strong positive or negative surface charge; it results in reduced stability span of dispersion through flocculation or aggregation by particles [107]. The pH of the dispersion is the factor that mostly affects the zeta potential [108].

      1.6.3 Thermal Analysis

      To examine lipid and lipid carriers’ “thermal behavior,” a thermal gravimetrical analysis (TGA) and differential scanning calorimetry

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