**2. General methods for polymeric nanoparticles preparation**

Recently, various kinds of polymers are used to prepare the polymeric nanoparticles, among this all polymer biodegradable polymers and their co-polymers such as di-block, tri-block, multi-block or radial block copolymer structures have been generally used to prepare poly‐ meric nanoparticles and to encapsulate the active ingredients. These multi-functionalized polymeric nano-carriers include micelles, capsules, platelets, fibers, spheroids colloids, dendrimers, core-shells, nanoparticle incorporated polymer matrixes, etc. The first polymeric nanoparticles were developed between the year of 1960 to 1970 for the therapeutic application, and this were Micelles[10-12].The micelles are formed by polymerisation methods, commonly the formation of polymer nano-carriers during the polymerization of monomers [13-16]. Then the various advanced polymerization techniques have been developed for the preparation polymeric based nanoparticles, and the nanoparticles were stabilised using various surfactants [1, 9]. The stabilised drug loaded nanoparticles consist of drug and non-toxic biocompatible polymer with stabilizing agents, the biocompatible polymer is either biodegradable or nonbiodegradable. Numerous techniques are available for the preparation of the polymeric nanoparticles and mainly top-down and bottom up processes. The polymer nanoparticle drug carriers can be further categorized into nano/micro-capsules and nano/micro-spheres depends on the size and structure [1, 9, 17-19]. The fine particles are 100 - 2,500 nm and ultrafine particles are 1 to100 nm in size, and are collectively known as nanoparticles. 50 to 300 nm sized

nanoparticle have been prepared by emulsion polymerization method [20]. Drawbacks in polymerization techniques are evolving noxious factors such as toxic, reactive residues, unreacted monomers, the risk of a chemical reaction and the formation of unwanted oligomers [1], and these drawbacks are overcome by using preformed polymers for the polymerization process [1]. Generally the drug loaded nanoparticles were prepared by dissolving the drug and polymer into the water-immiscible organic solvents and producing a nano-emulsion, as an example by probe-sonication method. The organic solvent is removed by using elevated temperature or reduced pressure [21-23], as an example of rotary evaporation method, and the nanoparticle is washed and collected by certification. Followed by various changes and improvements of the emulsification techniques have been reported [24-29]. For example, the sonication process is a crucial step in the preparation of the sensitive drug loaded nanoemul‐ sion, and the sonication process can increase the temperature, that leads to inactivate the active ingredients. In order to avoid the problems researchers utilized an on/off cycle to maintain a low temperature. Other examples of general methods to prepare the drug polymer nanopar‐ ticle are described in the Figure 1. The biodegradable polymeric nanoparticles are commonly prepared by five different techniques such as emulsification-solvent evaporation, solvent displacement, salting-out, emulsification-solvent diffusion and double emulsion solvent evaporation. The synthesizing methods include salting-out method [1, 30, 31]; it is based on the separation of a water miscible solvent from aqueous solution through the salting out effect, solvent displacement method [1, 32-34], phase separation method [35], evaporation precipi‐ tation [36, 37], antisolvent precipitation and electrospray methods [38].

Also, many approaches have been developed for the drug particle size reduction (in‐ crease in the surface) to the nanometer size range. For size-reduction, high pressure homogenization or wet bead milling is frequently used technique to produce reduced size nanoparticle [39-43]. Among these the high-pressure homogenization has been shown to be effective methods to produce size reduction particle. Moreover, its need sophisticated equipment to resist increasing pressures and temperature. Then, in order to obtain dried polymeric nanoparticle formulations researchers used various drying techniques such as atmospheric freeze drying, spray freeze drying, vacuum freeze drying, and lyophilisation. The uniformity of spray-dried nanoparticle is better than a freeze-dried nanoparticle. Moreover the lyophilisation and spray-drying are used to prepare the nanoparticle [44, 45], these nanoparticles easily tends to aggregates. Also the polymeric nanoparticles have also been synthesized by supercritical fluid techniques [46-52]. This method can get a dry product without any solution, also no need additional drying stages, but the supercritical fluid can swell some of the polymers and act as a softener, extender, and lubricant, which lead to aggregation. Moreover, this method is not easy to get the mono-dispersed multicomponent particles because of different kinetics [52]. Nanoparticles prepared by spraydrying technique are one-step based on the conversion of a droplet to a dry particle by evaporation [53-55]. These one-step techniques have been revealed that the nanoparticle could be prepared without any problems [56-58], and the drug content in the particles is almost high [59], but produce an amorphous residual structure. In all above technique induce some unwanted noxious factors, as well as the organic solvents used in the preparations are increasing the risk of pharmaceutical application, also the increased processing time leads to microbial contamination [60, 61, 62]. Understanding the all risk factors, recently the modern instrument provides a promising and viable platform for the

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preparation polymeric nanoparticles.

**3. Modern methods for preparation of polymeric nanoparticles**

Recently, the polymeric nanoparticles have emerged as a most promising and viable technol‐ ogy platform for recognizing the targeted, environment-responsive and, multi-functional with navigated controlled drug delivery system. Polymer in smart drug delivery is a rapidemerging new technological discipline in which various therapeutic applications of nano products are expected to overcome the patient complaints in healthcare. Smart delivery will give new solutions for therapeutic interventions. There is great interest from the beginning in smart medicine of advanced and well-characterized bionanotechnological products that will be especially effective in fighting diseases like cardiovascular diseases [63], diabetes [64], cancer [65, 66], aging [67, 68], some chronic metabolic syndrome and various degenerative diseases and disorders [69, 70]. For example, the innovative smart polymers with nanoparticulate drug-delivery systems can obviously advances in therapeutics by guiding the drugs to target cells and reducing the adverse-effect/side-effect on well being. At present, some of the smart polymer with multi-functioned nanoparticle system approaches in clinical trials, and it shows promising outcome. Certainly the morbidity and mortality rate of disease affected

**Figure 1.** General methods of preparation of polymeric nanoparticles and their principle involved in the mechanisms

Also, many approaches have been developed for the drug particle size reduction (in‐ crease in the surface) to the nanometer size range. For size-reduction, high pressure homogenization or wet bead milling is frequently used technique to produce reduced size nanoparticle [39-43]. Among these the high-pressure homogenization has been shown to be effective methods to produce size reduction particle. Moreover, its need sophisticated equipment to resist increasing pressures and temperature. Then, in order to obtain dried polymeric nanoparticle formulations researchers used various drying techniques such as atmospheric freeze drying, spray freeze drying, vacuum freeze drying, and lyophilisation. The uniformity of spray-dried nanoparticle is better than a freeze-dried nanoparticle. Moreover the lyophilisation and spray-drying are used to prepare the nanoparticle [44, 45], these nanoparticles easily tends to aggregates. Also the polymeric nanoparticles have also been synthesized by supercritical fluid techniques [46-52]. This method can get a dry product without any solution, also no need additional drying stages, but the supercritical fluid can swell some of the polymers and act as a softener, extender, and lubricant, which lead to aggregation. Moreover, this method is not easy to get the mono-dispersed multicomponent particles because of different kinetics [52]. Nanoparticles prepared by spraydrying technique are one-step based on the conversion of a droplet to a dry particle by evaporation [53-55]. These one-step techniques have been revealed that the nanoparticle could be prepared without any problems [56-58], and the drug content in the particles is almost high [59], but produce an amorphous residual structure. In all above technique induce some unwanted noxious factors, as well as the organic solvents used in the preparations are increasing the risk of pharmaceutical application, also the increased processing time leads to microbial contamination [60, 61, 62]. Understanding the all risk factors, recently the modern instrument provides a promising and viable platform for the preparation polymeric nanoparticles.

nanoparticle have been prepared by emulsion polymerization method [20]. Drawbacks in polymerization techniques are evolving noxious factors such as toxic, reactive residues, unreacted monomers, the risk of a chemical reaction and the formation of unwanted oligomers [1], and these drawbacks are overcome by using preformed polymers for the polymerization process [1]. Generally the drug loaded nanoparticles were prepared by dissolving the drug and polymer into the water-immiscible organic solvents and producing a nano-emulsion, as an example by probe-sonication method. The organic solvent is removed by using elevated temperature or reduced pressure [21-23], as an example of rotary evaporation method, and the nanoparticle is washed and collected by certification. Followed by various changes and improvements of the emulsification techniques have been reported [24-29]. For example, the sonication process is a crucial step in the preparation of the sensitive drug loaded nanoemul‐ sion, and the sonication process can increase the temperature, that leads to inactivate the active ingredients. In order to avoid the problems researchers utilized an on/off cycle to maintain a low temperature. Other examples of general methods to prepare the drug polymer nanopar‐ ticle are described in the Figure 1. The biodegradable polymeric nanoparticles are commonly prepared by five different techniques such as emulsification-solvent evaporation, solvent displacement, salting-out, emulsification-solvent diffusion and double emulsion solvent evaporation. The synthesizing methods include salting-out method [1, 30, 31]; it is based on the separation of a water miscible solvent from aqueous solution through the salting out effect, solvent displacement method [1, 32-34], phase separation method [35], evaporation precipi‐

260 Application of Nanotechnology in Drug Delivery

tation [36, 37], antisolvent precipitation and electrospray methods [38].

**Figure 1.** General methods of preparation of polymeric nanoparticles and their principle involved in the mechanisms
