METHODS OF PREPARATION OF NANOPHARMACEUTICALS

Nanoformulation is an important carrier for novel drug delivery system and prepared via several methods such as melt homogenization, precipitation from solvent in water emulsion, solvent evaporation, co-solvent evaporation, emulsification process, etc.

MELT HOMOGENIZATION

Melt homogenization is a simple and easy method of preparation of nanoparticles by use of high-pressure homogenization followed by size reduction using ultrasonication (Hussaini, Solorio, and Young, 2016). This method is generally used in formulation of solid lipid nanoparticle and nanostructure lipid carriers (Figure 10.13).

Preparation of nanoparticle by hot melt homogenization technique

FIGURE 10.13 Preparation of nanoparticle by hot melt homogenization technique.

SOLVENT EVAPORATION METHOD

In solvent evaporation technique, the drug along and polymer are dissolved in organic solvent having minimum boiling point then further this solution containing polymer and drug is subjected to evaporation to remove the organic solvent to form the thin film, this is followed by dehydration of formed film to form the nanoparticles. The formation of nanoparticles by this method dependent on various factors such as concentration of drug and polymer, nature of solvent and evaporation rate (Desjardins et ah, 2015). The main limitations of this process are that there is limited option available for solvent selection and redispersibility of formulation with the aqueous medium has to be considered during formulation. This technique is mainly used in the fonnulation of polymeric micelle.

CO-SOLVENT EVAPORATION

In co-solvent evaporation technique the aqueous system is directly pour into the non-aqueous (organic) solvent that ultimately results in formation of self-assembled micelles and promote encapsulation of drugs. The formation of nanoparticle is affected by many factors such as nature of solvent, the concentration of aqueous system and API, ratio of aqueous and non-aqueous solvent and solvent evaporation rate. The main drawback of this technique is difficulties in selection of solvent. Along with this drawback this technique has an important feature that high drug loading efficiency can be achieved.

PRECIPITATION FROM SOLVENT IN WATER EMULSION

The precipitation from solvent-in-water emulsion method is preferred in formulation of SLN and NLC (Desjardins et ah, 2015). The process and steps involved in this method are shown in Figure 10.14.

EMULSIFICATION PROCESS

This method is generally used in formulation of nanoparticle either by single emulsion process or by double emulsion process.

Precipitation from solvent-in-water emulsion

FIGURE 10.14 Precipitation from solvent-in-water emulsion.

SINGLE EMULSION

In single emulsion technique firstly polymer and drug are solublize in non- aqueous solvent. This solution is further emulsified with water-miscible solvents containing a surfactant. This method can be used to encapsulate the lipophilic drug moieties. Emulsification process is done by using high- pressure homogenization and sonication and the oil-in-water emulsion (O/W) is formed subsequently as soon as the organic solvent is evaporated from the system (Olugemo et al., 2015).

DOUBLE EMULSION

The double emulsion technique is generally applicable for the incorporation of hydrophilic drugs and water-in-oil-in-water (W/O/W) emulsion is formed. Hydrophilic drug is solubilized in an aqueous solvent followed by incorporation aqueous drug solution in polymer solution that leads to the formation of primary emulsion (Olugemo et al., 2015). This prepared primary emulsion is then added into the water-miscible system containing a surfactant to form a secondary emulsion and eventually subsequent evaporation of organic solvent leads to the formation of the desired emulsion.

CHARACTERIZATION TECHNIQUES OF NANOPARTICLES

Nanoformulations are usually characterized to seek infonnation regarding surface morphology, particle size, zeta potential, crystallinity, and drug excipients interactions by using various characterization methods as described below (Figure 10.15).

Characterization teclmique of nanoparticles

FIGURE 10.15 Characterization teclmique of nanoparticles.

PHOTON CORRELATION SPECTROSCOPY (PCS)

a) Particle Size Determination and Particle Distribution Index

Dynamic light scattering (DLS) analyses the constant changing pattern of laser light due to the diffraction which is attributes to the Brownian motion of nanoparticle. The particle size and the poly- dispersity index (PDI) of are determined using DLS on the basis of fluctuations in intensity of laser light (Zeng et al., 2010). In the case of lyophilized samples, it is first diluted to an appropriate concentration with triple distilled deionized water. The samples are analyzed at 25°C temperature with an angle of detection of 173 degrees. The particle size and PDI were determined by the instrument zeta sizer (Malvern Instruments, Malvern, UK), which works with the principle of DLS.

b) Zeta Potential

Zeta potential measures electrical charges lying on the surface of nanoparticle. Zeta potential is representative of stability of dispersion systems (Goldburg, 1999). It measures the potential difference between the bulk of fluid in which particles are dispersed and surface of nanoparticle containing opposite charge. Zeta potential with value more than ±40 indicates high stability of the dispersion system (Hanggi et al., 2016).

UVVIS1BLE ANALYSIS

The UV-Visible spectrophotometer is an important technology and mostly used for optimization of gold and silver nanocomposites. It is having capability to measure shape, concentration, size, refractive index and agglomeration state (Desai et al., 2012). This technique is also used to quantify and measure the active pharmaceutical ingredient entrapped in the nanoparticle (Goldburg, 1999). Bimetallic nanoparticle is characterized by comparing the spectrum with physical mixtures of monometallic nanoparticles (Contreras-Caceres et al., 2013).

FOURIER TRANSFORM INFRARED SPECTROSCOPY (FTIR)

FTIR technique is important for investigation of the surface chemistry of nanoparticles and functional group determination of those materials involved nanoparticle preparation (Movasaghi et al, 2008). The FTIR spectrum reveals information about nature of bond, existence of specific functional groups and interaction between nonfunctional groups in 400-4000 cm-1 wavelength region. IR spectroscopy is useful to characterize the multifunctional Fe hybrid, Ag and Au nanoparticles (Sheny, et al., 2011).

NUCLEAR MAGNETIC RESONANCE (NMR)

NMR is very essential analytical technique which is having application for elemental structure determination of nano-scale substances (Rangareddy, Mohanaraju, and Subbaramireddy, 2013). It is useful for the characterization of ferric and ferromagnetic materials due to the large magnetic saturation of such materials and applied for monitoring adsorbed gases diffusion from metallic nanoparticles. It is very decisive tool for reaction steps monitoring during polymer synthesis which is an integral materials for nanoparticle fabrication (Guo, Zhou and Lv, 2013).

TRANSMISSION ELECTRON MICROSCOPY (ТЕМ)

ТЕМ is a high power image magnification tool. Images are magnified by using beam of electrons that are transmitted through the sample. Rather than using light, electrons are used for illuminating the particles which result in high resolution of images (Folarin, Sadiku, and Maity, 2011). Transmission electron microscopy helps in the determination of the particle size of metallic nanoparticle (Gutowski, 1954). For the detennination of the size of solid lipid nanoparticles, at the first aqueous diluted suspension will be prepared followed by ТЕМ analysis. ТЕМ imaging also applied for the measurement of average particle diameter and size distribution of formulated samples (Johnson, 1999).

SCANNING ELECTRON MICROSCOPY (SEM)

SEM involves focusing of high-energy beam electrons on the sample which provokes a variety of signals at the outer layer of a solid sample, these scattered signals are collected by the detector for the imaging purpose. SEM discloses the information about the sample such as chemical composition, surface morphology and crystalline nature of the sample (Williams and Carter, 1996). SEM is used to investigate the outer surface of nanoparticles. The area which can be observed under SEM is around 5 pm to 1 cm in width. The sample preparation for SEM analysis, gold-plated conductors are used to sputter-coat at 11 mA for 50 s to deposit a thin layer on top of the sample (McDowell et al., 2012).

X-RAY SPECTROSCOPIC ANALYSIS

POWDERED X-RAY DIFFRACTION (PXRD)

PXRD is an unique analytical method, which is used chiefly in research and development for the determination of crystallinity traits of a compound or nanomaterial and capable to supply exact information on single-cell magnitude (Wang, 2000). The analyzed material is finely crushed and the size is reduced, followed by the determination of average bulk composition (Sokolova et al., 2011). The intensity of peak within the lattice is determined as a function of atom dispersion in the subjected sample (Liu, 2005). In XRD analysis, generated properties of x-ray diffraction patterns provide an exclusive “fingerprint” of the crystals within the presented sample. Consequently, interpretation of peak intensities is compared to reference materials pattern accompanied by measurements, this fingerprint allows researchers to identify the crystallinity (Bunjes and Unruh, 2007).

SMALL-ANGLE X-RAY SCATTERING (SAXS)

The small angle x-ray scattering studies mainly used for phase identification in the internal structure of nanoparticles and reveals information about nanoparticle size distribution and nanoparticles pore size. It works on the principle of elastic scattering behavior of x-rays when travel through materials at 0° to 10° angle. SAXS has enormous advantages over other crystallographic techniques (Akbari, Tavandashti, and Zandrahimi, 2011).

DIFFERENTIAL SCANNING CALORIMETRY (DSC)

Differential scanning calorimetry is a thermal technique applied for multiple purposes in various research and scientific organization to cany out quality in research work. It provides structural relevant information on the dispersed particles in a given sample. DSC offers several scientific measurements including glass transition temperature, reaction temperature, heat of the fusion, melting temperature, etc. (Ingham, 2015). This technique is more popular in phannaceuticals industries especially in research and development where large number of sample has to be investigated like analysis of number of chemicals, drugs analysis, polymers attributes, rubbers, metals, crystals in liquid samples followed by oxidative stability studies. It exhibits many crucial properties such as nature and crystallinity of the samples when compared to other existence calorimetric techniques (Bunjes and Unruh, 2007). DSC is able to screen and quantify the little changes in the thermal events in the sample. The measurement of energy absorbed or liberated by the particular sample during heating and cooling operation is based on DSC. In DSC, the sample of reference material and representative material are exposed at the same level of temperatures and the differences between the heat flow rate of the formulated sample and reference materials are measured and the result is interpreted.

THERMOGRAVIMETRICANALYSIS (TGA)

Thermogravimetric analysis is a technique applied to measure the thermal stability of samples (i.e., nanoparticles). The small modifications in physical and chemical properties of nanomaterials can be assessed either as a function of temperature where temperature varied with the constant heating rate or as a function of time where time is varied with constant temperature (Lin et al., 2014). The graph of TGA is a plot of mass change vs temperature or time which is categorized into seven types of curves based on stages of mass loss (Ingham, 2015) (Table 10.4).

TABLE 10.4 Techniques for Characterization of Nanoparticles

Technique

Parameters

References

XRD

Nature of crystal their composition and structure, size

Wang, 2000

FTIR

Nature of hydrogen bonding, ligands binding, and surface composition

Sheny et al., 2011

NMR

Atomic composition of formulation, ligands density, and arrangement, effects of ligands on nanoparticles shapes, elemental and chemical composition, growth kinetics

Rangareddy, Molianaraju, and Subbaramireddy, 2013

TGA

Stabilizer composition

Lin et al., 2014

DLS

Hydrodynamic size of particles and information about agglomerates

Hanggi et al., 2016

XPS

Composition of elements, electronic structure, and oxidative states.

Miele et al., 2009

ТЕМ

Detect formulation monodispersity, shape, aggregation states, internal structural information, dispersion of NPs in matrices, growth kinetics

Folarin. Sadiku, and Maity, 2011; Gutowski, 1954

AFM

Detect structure and shape in 3D mode

Hanggi et al., 2016

SEM

Information about morphology, detection of nanoparticles, size distribution

Johnson, 1999

PCS

Surface charge, agglomeration states, polydispersity index, size

Zeng et al., 2010

DSC

Detect density, size

Ingham, 2015

BET

Specific surface area

Zeng et al., 2010

 
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