INTRODUCTION:

Polymeric nanoparticles are natural or manmade polymer structures that are solid and spherical (in most cases). One of the top biomedical applications of polymeric nanoparticles is drug delivery. Polymeric nanoparticles have used to transport a variety of medications, including tiny hydrophilic and hydrophobic pharmaceuticals, vaccinations, peptides, and biological macromolecules, through a variety of ways.¹ PNPS have size range 1 to 100nm and probably been the max investigated nanocarrier among the many nanocarriers, with the goal of achieving greater therapeutic performance in the oral delivery area as well as other administration modes.

The widespread interest in employing PNPs as drug delivery systems can be attributed to three key factors. To begin with, when compared to alternative nanocarriers like liposomes or other lipid-based carriers, well-formulated PNPS have a high level of stability in the Gl milieu.² NPS have been examined as a vehicle to shield the encapsulated drug from numerous causes of deterioration due to their stability (e.g., acidic pH, digestive enzymes). Second, by carefully selecting a polymeric composition with a defined release kinetic, drug release can be precisely predicted and regulated. In fact, the nature of the polymer, specifically its degradation rate, molecular weight, and potential interactions with the medication, influence the profile and mechanism of drug release. Last but not least, the vast array of polymeric materials available for nanoparticle creation and modification enables polymer engineers and chemists with nearly limitless options for creating advanced and sophisticated therapeutic PNPs³.

Polymeric materials have distinct properties that make them ideal for drug delivery: they are highly stable and come in ample range of forms, allowing for a lot of design flexibility. Because of these features, they are widely used in a variety of medicinal applications. They enable for the loading of a broad range of APIs, including small compounds, nucleic acids, and biologics, as well as drug release kinetics control. The use of polymers provides easy modification of the nanocarriers physicochemical features (e.g., size, surface charge) as well as chemical functionalization via ligand attachment. Antibodies, peptides, and small compounds that target tissue components or cellular receptors can also be attached to the surface to enable for particular interactions. Nanospheres, nanocapsules, polymeric micelles, nanogels, dendrimers, and drug-polymer conjugates are some of the polymeric-based nanostructure oral drug delivery methods that were developed as a result of these advantages.

Fig: 1 The different structures of these polymeric nanomaterials ⁴.

Nanospheres and nanocapsules:

Polymeric nanoparticles (PNPS) are nanometre-sized solid particles with the API encapsulated or adsorbed on the surface. Nanospheres, in which the drug is equally dispersed in the polymeric matrix, and nanocapsules, a reservoir-type of particle with a drug-enriched centre surrounded by a drug-poor outer polymeric layer, are used to classify PNPs. Nanocapsules have a numerous benefits over nanospheres, including larger drug loadings (and less polymer), better active molecule encapsulation, and reduced burst emission.

Nanospheres are particles that comprise a matrix (i.e., particles whose entire mass is solid and whose molecules may be adsorbed at the sphere surface or encapsulated within the particle⁵. Nanocapsules are vesicular structures that operate as a reservoir, containing entrapped chemicals in a cavity made up of a liquid core (oil or water) surrounding by a solid material shell.

Fig 2: Nanosphere and nanocapsule 6.

Polymeric micelles:

Polymeric micelles (PMS) are core-shell structures created by the self-assembly of amphoteric polymers, which are polymeric chains with both a hydrophilic and a hydrophobic component. Micelle production, also known as micellization, is based on a thermodynamic mechanism that is dependent on the polymer concentration in solution: these polymers exist as unimers at low concentrations. The loss of entropy generated by polymer construction is countered by a gain in entropy due to the liberation of solvent molecules formerly "bound" in the solvation chambers of the monomers as concentrations rise. The critical micelle concentration (CMC) is attained at this time, and unimers clump together to generate micelles. Typical CMC values of amphiphilic block copolymers in water are in the scale of 107 to 103 M and the sizes of micelles obtained are generally within 100nm. PMs have a round shape when the hydrophilic core is bigger than the hydrophobic block, while copolymers with larger hydrophobic blocks develop non-spherical structures like rods and lamellae or polymeric vesicles⁷.

Nanogels:

The name "nanogels" refers to three-dimensional structures of chemical or physically cross-linked hydrocolloids that are nanoscale in size. A typical hydrogel is made up of a tiny amount of solid components, usually a bridge polymer, that are spread in a vast amount of liquid. The polymeric strands are hydrated but not soluble in the "swelled" state, and the system's characteristics lie somewhere between solids and liquids. Because of their capacity to achieve easy and high drug loadings, which is a very great bonus for nanocarriers, these systems are particularly promising for pharmaceutical applications. Self-assembly methods utilising electrostatic, Van der Waals, and/or hydrophobic interactions among both the bioactive compounds and the polymer can allow the drug to be loaded spontaneously. This technique produces collapsed nanogels, which are structurally similar to a stable nanoparticle suspension in which the active chemical is confined in liquids.⁸

Dendrimers:

Polymeric macromolecules known as dendrimers. They have a well-defined shape with a central core (made up of an atom or molecule) and many symmetrically emerging branches from the core, forming a circular three-dimensional globular shape⁹. Dendrimers are a certain type of nanostructure with a highly branching three-dimensional nanoscale geometry and minimal polydispersity. Dendrimers are made up of many branched homologous fragments (called dendrons) that radiate radially from a central core, resembling the tree-like conformation from which they get their name (Greek, dendra). The most commonly used substance for dendrimer synthesis is poly(amidoamine) (PAMAM). Drug molecules can be encased in the dendritic hydrophobic core of the sphere or bonded to ligands on the dendrimer surface. Dendrimers of various compositions have been studied as drug carriers for a variety of routes of delivery, including parenteral, transdermal, and oral. PAMAM dendrimers can penetrate through the intestinal epithelium in several investigations, suggesting that they could be used to solve permeability issues¹⁰.

Because of the inclusion of amine groups, dendrimers have restricted clinical applicability. Because these compounds are positively charged or cationic, they are harmful; as a result, dendrimers are frequently changed to lessen or remove the toxicity issues. Simple encapsulation, electrostatic contact, or covalent conjugation can all be used to load drugs into dendrimers ¹¹.

Polymer-drug conjugates:

Drug targeting including one or even more therapeutic agents, like biomolecules, peptides, or proteins, covalently bonded to a polymer backbone are known as polymer-drug conjugates. These macromolecular systems are made of a water-soluble polymeric carrier (typically between 10,000 and 100,000 Da) that is linked to the active participant by a biodegradable polymer-drug coupling, which is commonly a peptidyl or ester linkage. Unlike other polymer-based nanocarriers, regulatory authorities consider polymer-drug conjugates to be "novel chemical entities" since the API is covalently changed rather than just non-covalently entrapped in a vehicle¹².

Low-molecular-weight medicines are covalently linked to a biocompatible hydrophilic polymer to produce a polymer drug conjugate. Following administration, an enzyme present at the administration site digests the polymer drug conjugate, releasing a therapeutic substance. The pharmacokinetic disposition of the medication in the whole body and at the cellular level changes dramatically as a result of this interaction/conjugation. The polymer vehicle is used to carry medications, boost their water solubility, and prevent cargo from being expelled from the body too quickly. They're made to have a higher total molecular weight, making their increased permeation and retention (EPR) impact easier¹³.

Polymers used in nanoparticle:

Natural polymer:

Naturally occurring biodegradable polymers has been used in biomedical applications, due to its copious in nature and biocompatibility, and comprise protein-based polymers, such as collagen, ‘albumin’, ‘gelatin’, and ‘polysaccharides’, such as ‘agarose’, ‘alginate’, ‘carrageenan,’ hyaluronic acid (HA), ‘dextran’, ‘chitosan’, and ‘cyclodextrins’.

Fig 3: Structure of some natural polymer ¹⁴.

Chitosan:

The use of biodegradable polysaccharides in medication delivery has showed promise. Chitosan, which is generated from the chitin naturally present in crustacean exoskeleton, is a significant polysaccharide with a wide scale of applications¹⁵. Chitosan is made by deacetylation chitin, which results in the formation of primary amine compounds, which make the polymer cationic in diluted acidic conditions. As a result, chitosan binds and complexes electrostatically with negatively charged macromolecules like nucleic acids to create polyplexes. The positive charge of chitosan promotes cell absorption and attachment to negatively charged mucosal surfaces, making it ideal for medication administration. Decomposition can be fine-tuned for biological applications by adjusting molecular weight, deacetylation degree, and chemical modifications¹⁶.

Wound dressing and curing (which signify anti-inflammatory properties), gene delivery, oral and pulmonary delivery (due to mucoadhesive properties) are all main applications of chitosan.

Dextran:

Dextran is a branching polysaccharide made up of simple a-D-glucose repeat units linked by glycosidic linkages. Dextran is a hydrophilic, water-soluble polymer that can be acetylated to produce AcDex, a hydrophobic polysaccharide. It's usually coupled with crosslinkers to generate a hydrogel or coating for drug delivery. Dextran can also be coupled as a block copolymer to a hydrophilic polymer like PEG, poly(e-caprolactone) (PCL), or polylactide (PLA) to generate amphiphilic micelles that can be filled with hydrophobic medicinal drugs¹⁷.

Gelatin:

Gelatine is a peptide and protein combination made from the hydrolytic cleavage of bovine collagen. It's nonimmunogenic, biocompatible, and commonly used in food and cosmetics. As a result, gelatin nanoparticles have been studied for the transport of nucleic acids and small molecule drugs to malignancies. The isoelectric point of gelatin can changed to improve drug loading, and the molecular weight and crosslinking density of gelatin can changed to manage drug release¹⁸.

Alginate:

Alginate is a hydrophobic material extracted from algae that is economical and naturally generated. It's made up of blocks of B-1, 4-linked mannuronic acid, and it's rectilinear and unbranched α (1-4) guluronic acid residues that are connected¹⁹. Alginate is anionic, and adding divalent cations like calcium causes it to gel. Because of the hydroxyl and carboxyl groups on the backbone, it can be easily functionalized, allowing its chemical and biological properties to be tailored. Alginate is a biocompatible and nonimmunogenic material that is utilised in a variety of FDA-approved products, ranging from food supplements to wound treatments²⁰.

Poly (L-lysine):

The polymerized version of lysine, a cationic amino acid, with stereochemistry for natural enzymatic degradability is known as poly(L-lysine) (PLL). PLL may efficiently condense negative charges molecules into nanoparticles because of the polymer's high positive charge density. PLL is frequently employed as a coating on core-shell nanoparticles because its positive charge increases particle absorption. PLL can be made in both linear and dendritic forms, with dendritic PLL having better buffering and nucleic acid transport capabilities²¹.

Table 1: Some examples of Natural polymer loaded Nanoparticle

Type of Polymers	Formulated Drug/ Bioactive	Method of preparation	Applications purpose	Ref.
Chitosan	Carvedilol	Nanoprecipitation method	Antihypertensive	22
Dextran	Vitamin B12	Dialysis Crosslinking	Antidiabetic	23
Gelatine	Paclitaxel	Solvent Evaporation method	Anticancer	24
Alginate	Enoxaparin	Ionic gelation method	Anticoagulant	25
Poly(L-lysine)	Bufaline	Emulsification method	Anti-tumor	26

Synthetic polymer:

Fig 3:Structure of some synthetic polymer ²⁷

Poly(esters):

PLGA Polymers:

Polyesters are carbon-based polymers having ester bond connections. The aliphatic polyesters, which comprise PGA, PLA, and PLGA, are thoroughly studied biodegradable polymers to date. PLGA is made by ring-opening polymerization (ROP) of cyclic lactide and glycolide monomers and it dissolves in water catalyse the hydrolysis of its ester linkages. Aliphatic polyesters can be made from a wide variety of monomers, and polycondensation of difunctional monomers gives low-MW polymers. For high-MW polymers, ROP is utilised. ²⁸ The simple rectilinear aliphatic polyester is PGA, which has low solubility in organic solvents due to its high crystallinity (45-55 percent). With a Tg of 35-40 °C, PGA offers excellent mechanical characteristics.²⁹ Because PGA's limited solubility and rapid breakdown into glycolic acid make it a poor choose for polymeric NP in therapeutic applications, copolymers of PGA, such as PLGA, were developed.

Polycaprolactone:

Poly(caprolactone) (PCL), which is produced from the ROP of e-caprolactone using a tin octoate catalyst, is extensively used biodegradable aliphatic polyester in drug carriers. PCL is a semirigid material at room temperature because of its high solubility and low Tg (about -60°C). PCL has been used more in tissue regeneration as a scaffold matrix material than in particulate-based medication delivery to date. 88 The scarcity of solubility and excruciatingly slow degradability (2-3 years for pure PCL) are one cause for this; nevertheless, modifying PCL with other polymers (such as block polymer synthesis or blending with PLGA and PLA) has improved its decomposition and reactivity. The manufacturing of PCL block copolymers result from amphiphilic configuration and various mechanical and physical characteristics³⁰.

Poly (alkyl cyanoacrylates):

Poly(alkyl cyanoacrylates) (PACAS) are made from alkyl cyanoacrylate monomers and used in therapeutic applications, are a type of biodegradable polyester. Rapid polymerization reactions are facilitated by the residence of two highly reactive electron-withdrawing category on the alkyl cyanoacrylate monomers. These polymerization reactions are normally carried out in aqueous medium, with the hydroxide ion serving as the activator.³¹ PACAS can be made from alkyl cyanoacetate using either the Knoeveagel condensation synthesis, which produces oligomers, or a thermal depolymerisation method. Zwitterionic polymerization has used to make diblock and triblock copolymers with PEG and PACA blocks³². PACAS-made NPs have progresses the most, and these passively targeted NPs are presently in phase III clinical trials for a broad variety of applications.

Poly(anhydrides):

Poly(sebacic acid), poly(adipic acid), and poly(terphthalic acid), among others, are poly(anhydrides). Surface erosion occurs in poly(anhydrides), and the release kinetics are determined by the characteristics of the drug payload and intrinsic dissolving kinetics. The breakdown of polyanhydrides is the key element in the discharge of a hydrophobic drug, whereas solute transport is reliant on the concentration difference between the distribution system and the external surface in the case of a hydrophilic drug.³³ When researching poly(anhydride) drug delivery, both drug solubility and polymer solubilization must be taken into account.

Poly (ortho esters):

Poly(ortho esters) (POES) are hydrophobic surface-eroding polymers that were developed in the 1970s as synthetic polymers for use as sutures in surgery. They are classified into four categories and generally have three geminal ether bonds.³⁴ POES are degradable and normally release compounds through diffusion mechanisms; drug release is initiated by hydrolysis of polymer chains on the matrix's outer shell. The inclusion of acidic excipients has been proven to speed up the hydrolysis process. Furthermore, basic excipients can maintain the bulk material while diffusing out of the surface layer, causing surface erosion.³⁵ As a result, altering the acidity/basicity provides for some command over the timing of the release. POES are steady at physiological pH; however, as the intestinal pH drops to around pH 5, they become unstable. Despite the fact that orthoester linkages are very reactive in nature, polymers containing these linkers are water insoluble, allowing only a little amount of water to pass through. Because POE I hydrolyse quickly in water to form y-butyrolactone, which then changes to y-hydroxybutyric acid, it is no longer used in clinical applications. POE II is hydrophobic since it has a low degree of water sorption and a Tg of 22°C (if based on 1, 6-hexanediol). At room temperature, 157 POE III is a semisolid, which allows for medication blending without the use of solvents or high temperatures. POE III has a lower hydrophobicity than POE II. A mono- or diglycolide segment is introduced into the polymeric chains of POE IV. As a result, lactic or glycolic acid units are formed, which promote the hydrolysis of further ester links in the polymer³⁶.

Poly(amides):

Poly(amino acids) are commonly used poly(amides) for medication administration. Their synthesis has previously been well investigated, making them an excellent mature base on which to build. Poly(amino acids) are commonly employed to generate low-MW medicines because they are largely innocuous, and because they are stable to hydrolysis. Poly(amino acids) breakdown rates are determined by the hydrophilicity of the amino acids that make up the polymer.³⁷ Polyamides are semi-crystalline in nature. Using side groups such as benzyl, hydroxyl, or methyl groups during copolymerization might speed up composting process. Most poly (amino acids) are composed of just one kind of amino acid, such as poly(α-glutamic acid) and poly(amino acid) (L-lysine).

Poly (ester amides):

PEAs are polymers containing both ester and amide connections on their backbones, resulting in mechanical and biological characteristics as well as enzyme-catalyzed degradability.³⁸, Poly(amino acids)-based PEAs with promising biological and pharmacological uses have been created by combining the beneficial features of polyesters and polyamides with poly(amino acids). Nontoxic structural units such as a-amino acids, fatty diols, and aliphatic dicarboxylic acids often make up the PEA backbone. The rate of depolymerisation through hydrolytic mechanisms is slow due to the alternating of amide and ester bonds in this biopolymer, and most of the reported faster degradation rates are catalysed by enzymes. These polymers are likewise very crystalline, and the Phe: Gly ratios can be adjusted to alter the rate of breakdown.³⁹

Poly(phosphoesters):

Poly(phosphoesters) are biocompatible and degradable polymers that can be used in medication delivery and tissue engineering. The phosphorus atom's pentavalency permits it to conjugate a variety of side chains, such as proteins or tiny medicines. The conjugation of distinct side groups also enables the polymers' physicochemical characteristics to be fine-tuned. Due to the conjugation of electrostatic interactions to the phosphate side chain, poly(phosphoesters) biodegrade through hydrolysis and enzymatic digestion and are ideal categories of polymers for nucleic acid delivery.⁴⁰ ROP, condensation, and addition polymerizations can all be used to make poly(phosphoesters), and their quick breakdown rates result in harmless compounds. Poly(phosphoesters) can be copolymerized with polyethers and polyesters for drug delivery applications and they acquire attention as biomedicine⁴¹.

Table 2: Examples of synthetic polymer loaded nanoparticle

Type of Polymers	Formulated Drug/ Bioactive	Method of preparation	Applications purpose	Ref.
PLGA	Nifedipine	Solvent Evaporation method	Antihypertensive	42
PCL	Isradipine	Nanoprecipitation method	Antihypertensive	43
PECA	Etoposide	Emulsion Polymerization	Antitumor	44
Poly (orthoester)	Celecoxib	Solvent diffusion method	Anti-inflammatory	45
Poly (anhydride)	cyclodextrin	Solvent Displacement method	Anticancer	46
Poly (ester amide)	Curcumin	Solvent evaporation method	Anti-angiogenesis	47
Poly (phosphoester)	Paclitaxel	Solvent Evaporation method	Antitumor	48

Method of preparation:

Numerous tactics for producing polymeric NPs can be used depending upon the nature of bioactive to be placed in them and their requirements for a specific administration route. The dispersion of premade polymers or the polymerizations of monomers are the two major techniques used in general. Organic solvents are often employed in the first step to dissolve the polymer in most procedures that require the usage of premade polymers. These solvents have the potential to cause issues with toxicity and environmental concern. Solvent remnants must also be abolished from the finished product. In order to load chemicals into polymeric NP S techniques that rely on monomer polymerization allow for more efficient insertion in a single reaction step. The products are frequently obtained as aqueous colloidal suspensions, regardless of the technique of manufacturing⁴⁹.

Solvent Evaporation:

The initial approach for making polymeric NPs from a premade polymer was solvent evaporation. The preparation of (o/w) emulsion is involved in this process, which leads to the development of nanospheres⁵⁰. To begin, an organic phase is made of a polar organic solvent in which the polymer is dissolved and the active ingredient is dispersed/dissolved. Dichloromethane, ethyl acetate, and chloroform are abundant organic solvents. The organic solution is emulsified in the aqueous phase with a surfactant (e.g., polyvinyl acetate; PVA), and then it is commonly treated by utilising high-speed homogenization or ultrasonication, generating a dispersion of nanodroplets⁵¹. The evaporation of the polymer solvent, which is allowed to spread into the dispersion medium of the colloid, creates an NP suspension. The solvent is removed either by constant magnetic stirring at room temperature (in the case of more polar solvents) or by a gradual, low-pressure process (in the instance of less polar solvents) (as happens when using e.g., dichloromethane and chloroform). The hardened nanoparticles can be purified and recovered by centrifugation once the solvent has dissipated, and then freeze-dried for prolonged storage. Nanospheres can be made using this method.⁵²

Fig 4: Diagram of Solvent Evaporation Method⁵³

Emulsification/Solvent Diffusion:

The production of an o/w emulsion among a partially water miscible solvent containing polymer and medicament and an aqueous phase with a stabilizer is the goal of this technique⁵⁴. A somewhat hydro-miscible organic solvent, such as benzyl alcohol or ethyl acetate, makes up the internal layer of this emulsion. The production of colloidal particles is generated by solvent diffusion from the dispersed droplets into the exterior phase after dilution with a large volume of water. This is the most common method for making nanospheres. Finally, according on the boiling point of the organic solvent, either evaporation or filtration can be used to eradicate the final stage. Despite the need for a large volume of aqueous medium to be removed from the colloidal dispersion and the possibility of hydrophilic drug diffusion into the water phase, this process is often used for the fabrication of polymeric NPs.⁵⁵

Fig 5: Diagram of Solvent Diffusion Method⁵³

Emulsification/Reverse Salting-Out:

The solvent diffusion method is a variation of the emulsification/reverse salting-out technique. The salting-out approach relies on a salting-out action to separate a hydro-miscible solvent from an aqueous solution, which can result in the creation of nanospheres⁵⁶. The key distinction is the composition of the o/w emulsion, which is made up of a gel, a salting-out substance, and a colloidal stabiliser in the aqueous phase, which is made up of a water-miscible polymer solvent like acetone or ethanol. Electrolytes, such as magnesium chloride (MgCl2), calcium chloride (CaCl2), or magnesium acetate [Mg(CH,COO)], along with non-electrolytes, including sucrose are examples of acceptable salting-out substances. Saturating the aqueous layer reduces the miscibility of acetone and water, allowing the creation of an o/w emulsion from the other miscible phases⁵⁷. The o/w emulsion is made at room temperature with vigorous mixing. The emulsion is then diluted with deionized water or an aqueous solution to facilitate for the diffusion of the organic solvent to the exterior phase, the precipitation of the polymer, and, as a result, the development of nanospheres. Cross-flow filtration removes the leftover solvent and salting-out reagent. Although total miscibility of the organic solvent and water is not required, it does make the execution process easier. The nanospheres produced by this process range in size from 170 to 900 nanometres. By adjusting the polymer content of the internal phase/volume of the exterior phase, the average size can be changed to values between 200 and 500nm⁵⁸.

Fig 6: Diagram of Reverse salting out Method

Nanoprecipitation:

Two miscible solvents are required for this approach, also known as the solvent displacement method. A polymer is dissolved in a miscible organic solvent, like acetone or acetonitrile, to form the internal state ⁵⁹. They can be quickly eliminated by evaporation due to their immiscibility in water. This method is based on the interfacial deposition of a polymer after the organic solvent has been moved from a lipophilic solution to the aqueous solution. The polymer is mixed in a water-miscible solvent with an intermediate polarity, and the solution is added to an aqueous solution sequentially (dropwise) or at a regulated rate. Nanoparticles develop instantly in an effort to evade water molecules owing to the rapid spontaneous diffusion of the polymer solution into the aqueous medium ⁶⁰. The polymer precipitates in the form of nanocapsules or nanospheres as the solvent diffuses out of the nanodroplets. The organic phase is usually introduced to the aqueous phase; however this can be reversed without impacting nanoparticle production. Surfactants are frequently used in the processing to ensure the stability of the colloidal suspension, while their inclusion is not needed for nanoparticle development.] Nanoprecipitation is a standard technique for producing polymeric NPs with diameters of roughly 170nm⁶¹.

Fig 7: Diagram of Nanoprecipitation Method ⁵³

Characterization of PNP’s:

Physical characteristics such as composition and concentration, and also size, shape, surface characteristics, crystallinity, and dispersion condition, can all affect polymeric NPs. These features are frequently evaluated using a variety of methodologies in order to fully characterise the NPs. Electron microscopy, ‘Dynamic light scattering’ (DLS) or ‘Photon correlation spectroscopy’ (PCS), near-infrared spectroscopy, electrophoresis, and chromatography are just a few among the most widely utilised techniques.

Morphology:

SEM and TEM (scanning and transmission electron microscopy) were extensively utilised to determine the shape and size of polymeric NPs. To undertake NPS morphological analysis, these are frequently paired with cryofracture procedures. The electron microscope (TEM) is broadly used and can make the distinction among nanocapsules and nanospheres, as well as discern the width of the nanocapsule wall⁶². Nanospheres have a spherical and a solid polymeric structure, whereas nanocapsules have an oily core consist of a thin polymeric envelope (about 5nm). Atomic force microscopy (AFM) is another technique that has been utilised to investigate the surface morphology of polymeric NPS. It provides high-resolution data in three dimensions and on a nanometric scale, as well as the ability to resolve atomic-level surface specifics⁶³.

Molar Mass Distribution of the Polymer:

During preparation, determining the polymer molar mass distribution can reveal information about the effect of excipient on the polymerization process, the existence of chemical reactions among the bioactive and the polymer, and the polymer's degradation. Size-exclusion chromatography (SEC) is the most widely used technique for measuring the polymer molar mass distribution⁶⁴.

Particle Size Distribution:

Polymeric NPs generated by diverse processes can have mean size in the range from 100 to 300nm. The size distribution should be unimodal and the polydispersity should be as low as feasible (ideally, nearly zero). It is also viable to generate particles with dimensions of 60 to 70 nm, or even less than 50nm. The most used approach for measuring nanoparticle size are dynamic (DLS) and static (SLS) light scattering, but TEM, SEM, and AFM are also frequently utilised⁶⁵. The size of a particle can vary regardless of the method used; for example, electron microscopy provides an image of the particle separated from its surrounds, whereas DLS enables the hydrodynamic radius of suspended particles to be determined. Furthermore, DLS is an essential contributor to TEM since it can detect bigger sizes, allowing researchers to learn about a nanoparticle's aggregation state in solution by monitoring the changes in particle size distribution⁶⁶.

Surface Area and Chemistry:

For its impact on reactivity and surface interactions with ligands, the surface area of NPs is important. Diverse methods are used to calculate various characteristics of surface area. The elemental or molecular chemistry of a particle surface is referred to as surface chemistry. Due to the greater area/volume ratio of nanoparticles, a higher number of atoms are on their surfaces, and these atoms are in direct contact with solvents, influencing their relationships with other molecules. The surface chemistry of nanoparticles can be studied using a variety of techniques, including X-ray photoelectron spectroscopy and secondary ion mass spectroscopy⁶⁷.

Zeta Potential:

The zeta potential (ζ) represents the particle's surface charge, which is associated with changes in the particle's interaction with the scattering media, such as uncoupling of functional groups on the particle's surface or adsorption of ionic species present in the aqueous dispersion medium, as well as the solvation effect. The zeta potential is calculated from the electrophoretic mobility of particles in a given solvent. This parameter is ascertained using Doppler method to evaluate particle velocity as a function of voltage. The core elements of polymeric NPs include phospholipids, poloxamers, and polymers, which, once incorporated in formulations, can influence the zeta potential. Large repulsions tend to avoid aggregation owing to periodic contacts with nearby nanoparticles, hence a massively good zeta potential value |± 30 mV|, is critical for optimal physicochemical durability of the colloidal suspension. The assessment of zeta potential is able to clarify the mechanism of drug-nanoparticle interaction ⁶⁸.

Stability of Polymeric NPs Suspensions:

The sedimentation process is sluggish for submicrometric particles and more limited by Brownian movement, colloidal suspensions normally do not phase separate until several months after formulation. Particle aggregation and sedimentation, on the other hand, may accumulate over time⁶⁹. The adhesion of active molecules on the surface of nanoparticles and the existence of adsorbed surfactants are two factors that can affect the longevity of colloidal suspensions. Particle size, zeta potential, polymer molar mass distribution, drug content, and pH are a few physicochemical variables that could be utilised to assess the durability of polymeric colloidal suspensions. Particle aggregation, polymer chemical stability, drug or other raw materials utilised in NPS manufacturing, and early release of the active component are the key limits. Spray drying, on either hand, as an option in contrast to lyophilization for enhancing the reliability of nanoparticles formed by solid lipids, entails passing the solution through an atomizing orifice, into the drying chamber as droplets, in a co-current, counter-current, or mixed flow of hot air, which endorses the quick drying of the droplets. The dry solids are subsequently isolated and collected, and fine powders, granules, or agglomerates can be produced⁷⁰.

Determination of the Drug Association:

Since of their tiny size, it is hard to distinguish the free fraction of the drug from the associated fraction when determining the amount of drug linked with nanoparticles⁷¹. Ultracentrifugation is an extensively used technique for separating in which the amount of free active ingredient in the suspension is evaluated in the supernatant post centrifugation. A fraction of the nanoparticles is usually completely dissolved in a suitable solvent to ascertain the total amount of drug. As a result, the disparity between total and unbound drug concentrations is used to estimate the drug concentration linked with nanoparticles. Ultrafiltration-centrifugation, wherein a membrane is employed to isolate portion of the dispersing aqueous layer from the colloidal suspension, is yet another approach that is used. In the ultrafiltrate, the unbound drug concentration is obtained, and the drug fraction related with nanostructures is derived by subtracting total and unbound concentrations ⁷²

pH of Suspensions:

Monitoring pH as a respect to time can provide good data on the longevity of nanoparticulate suspensions. Changes in pH, for example, may signify polymer degradation since they imply alterations in protonation at particle surfaces. Over 6 months of storage, a reduction in molar mass was observed in suspensions of nanocapsules and nanospheres, as well as a drop in the pH of these formulations⁷³. Even so, depending on the hydrophobicity of the polymer, the decline in pH values of suspensions in a short stretch of time can be ascribe to both the ionisation of carboxylic groups existing in the polymer, liberating protons into the surrounding medium, and the ionisation of carboxylic groups present in the polymer, liberating protons into the extracellular environment. Furthermore, because the pH of the solution might affect the zeta potential and electrostatic persistence of the composition, it is critical to keep track of it.

In vitro Release Kinetics:

The release rate of API from PNPs relay on desorption of bioactive from surface of the particles or polymeric matrix erosion, the diffusion of the drug through the nanosphere matrix or through the polymeric wall of the nanocapsules, or a conjunction of diffusion and erosion mechanisms determine release profile from polymeric NPs⁵¹. Release rate from polymeric nanoparticles has been described using techniques like diffusion from dialysis bags and segregation based on ultracentrifugation, low-pressure filtration, or ultrafiltration-centrifugation⁷⁴. Prior reports have demonstrated that the dynamics of drug release from nanospheres is often exponential (first order), presumably due to drug diffusion from the polymeric matrix to the environment and/or polymeric matrix degradation, releasing the drug. The medication immersed in the oily nucleus of nanocapsules would potentially be liberated from this vesicular form upon diffusion through the polymeric wall, resulting in zero-order kinetics⁷⁵.

CONCLUSION:

The preceding evidence suggests that nanoparticulate systems have significant promise for converting poorly soluble, poorly absorbed, and labile biologically active substances into efficient drug delivery systems. Diverse types of nanocarriers have been investigated for biomedical applications, but the bioavailability achieved with nanosized drug delivery systems, particularly in intravenous injection, is frequently low when compared to the total drug quantity in these systems. The primary needs for building more prosperous drug nanocarrier systems in the time ahead include detailed comprehension of the physicochemical characteristics of these nanocarriers, as well as a thorough understanding of biomembranes and their functions.

The only way to characterize these drug carriers physicochemically is to use a combo of analytical techniques. The elucidation of drug attachment processes to polymeric NPs remains one of the most difficult issues. Several breakthroughs have already been made, both in terms of accumulating knowledge about the physicochemical phenomena at hand and in terms of developing more stable polymeric NP formulations, which could widen the scope of therapeutic applications for these systems Although research interest in nanosized approach is growing, the number of commercially available nanomaterial-based solutions remains modest. Nanoparticle research is required to continue the development of effective nanocarriers that pose no damage to the environment or human health.

ACKNOWLEDGEMENTS:

The author intention to express their sincere thanks to the Honourable Principal and professors of Yashoda Technical Campus, Faculty of Pharmacy, (Wadhe) Satara for motivating and inspiring to write this futuristic article.

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Received on 08.04.2022 Modified on 05.05.2022

Asian J. Pharm. Tech. 2022; 12(4):371-381.

DOI: 10.52711/2231-5713.2022.00058