Nanoparticles Prepared by the Polymerization Process

Historically, the first methods used to produce nanoparticles were derived from the field of latex engineering developed by polymer chemists. These methods were based on the in situ polymerization of monomers in various media. In the early 1970s, Birrenbach and Speiser, the pioneers in the field, produced the first polymerized nanoparticles for pharmaceutical use. Two types of polymerization processes were adopted for the preparation of polymeric nanoparticles: dispersion polymerization (DP) and emulsion polymerization (EP).

15.2.1.1.1 Dispersion Polymerization

A DP involves a monomer, an initiator, a solvent in which the newly formed polymer is insoluble, and a polymeric stabilizer. The polymer is formed in the continuous phase and precipitates into a new particle phase stabilized by the polymeric stabilizer. The nucleation is directly induced in the aqueous monomer solution. Small particles are formed by the aggregation of growing polymer chains precipitating from the continuous phase when these chains exceed a critical chain length. When enough stabilizer covers the particles, coalescence of these precursor particles with themselves and with their aggregates results in the formation of stable colloidal particles. In this technique, the monomer is dispersed or dissolved in an aqueous medium from which the formed polymer precipitates.

Essentially, the initiation of a monomer for polymerization requires an initiator that can generate ions or radicals to start the polymerization process. If the nucleation of the monomer is due to ions, then the mechanism is called "ionic polymerization." Depending on the type of ions produced, the ionic polymerization may be anionic or cationic. If the radical nucleates the monomer, then the mechanism is known as "radical polymerization."10

15.2.1.1.2 Emulsion Polymerization

Emulsion polymerization is a method for producing a latex and a polymer that exhibit any desired morphology, composition, sequence distribution, surface groups, molecular weight distribution, particle concentration, or other characteristics. In this technique, the monomer is emulsified in a nonsolvent-containing surfactant, which leads to the formation of monomer-swollen micelles and stabilized monomer droplets. The polymerization is performed in the presence of an initiator. The initiator generates either radicals or ions depending on the type of initiator, and these radicals or ions nucleate the monomeric units and start the polymerization process. The monomer-swollen micelles exhibit sizes in the nanometer range and thus have a much larger surface area than the monomer droplets. It has been assumed that, once formed, the free reactive monomers would more probably initiate the reaction within the micelles itself. In this case, the monomer droplets would act as monomer reservoirs. Being slightly soluble in the surrounding phase, the monomer molecules reach the micelles by diffusion from the monomer droplets, thus allowing the polymerization to be continued in the micelles.11,12 Generally, the reaction continues until the monomer completely disappears. The particles obtained by EP are usually smaller (100-300 nm) than the original stabilized monomer droplets in the continuous phase. EP may be performed using either organic or aqueous media as the continuous phase.

Emulsion Polymerization in an Organic Continuous Phase. EP in the organic continuous phase was the first process reported for the preparation of nanoparticles.5,13 In this process, the water-soluble monomers are polymerized. Acrylamide and the crosslinker N,N0-bisacrylamide were the prototype monomers to be polymerized using chemical initiators such as N,N,N',N'-tetramethyl-ethylenediamine and potassium peroxdisulphate or by light irradiation by g- or UV-radiations. However, the high toxicity of monomers and the need for high amounts of organic solvents and surfactants limits the importance of this technique.

The cyanoacrylate monomers are relatively less toxic than acrylamide, and their polymers are biodegradable. Poly(alkyl cyanoacrylate) (PACA) nanoparticles were prepared by EP in the continuous organic phase. In this case, the monomer was added to the organic phase, creating nanoparticles with a shell-like structure (nanocapsules), as well as solid particles.14 The mechanism of this nanocapsule formation was explained as following. The drug dissolved in aqueous phase was solubilized in the organic phase (containing surfactants) such as iso-octane, cyclohexane-chloro-form, isopropyl myristate-butanol, and hexane. This result in a microemulsion with water-swollen micelles containing the drug. The monomer diffuse into the swollen micelles, and the OHK ions initiated the polymerization. The polymerization is so rapid that only an impermeable wall could be formed at the organic/water interface, preventing the diffusion of further monomers into the particles. The high amounts of organic solvents and surfactants required for this process, however, has greatly limited its application.

Emulsion Polymerization in an Aqueous Continuous Phase. This technique is widely used for the preparation of nanoparticles by the polymerization of a wide variety of monomers, including alkylcyanoacrylates. Employing very low quantities of surfactants, it is only used to stabilize the newly formed polymer particles. Apart from this, the polymerization of alkylcyanoacrylates has also been carried out in the absence of surfactants,15 in aqueous media containing dextran or hydroxylpropyl-b-cyclodextrin (HPCD). Poly(ethyl cyanoacrylate) and poly(isobutyl cyanoacry-late) (PIBCA) nanospheres containing metaclopramide have been prepared using this technique. However, the resulting drug loading was only 9.2% and 14.8%, respectively.

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