**1. Introduction**

Nanoprecipitation is a technique to incorporate active molecules into colloidal drug delivery systems, patented by Fessi et al. [1, 2], which attracts attention for developing pharmaceutical products mainly due to the simplicity of its procedure [3]. The obtained particles enable the optimization of the drug *in vivo* therapeutic performance exhibiting, for example, controlled release behaviors, target delivery, and better stability in biological fluids, which means major mean residence times, half-lives increased, and more efficient addressing of the actives toward the different body tissues. Consequently, less toxicity and minor secondary effects are expected.

Some of the research works undertaken during the last years have proposed the vectorization in nanoparticles, via nanoprecipitation, of hydrophobic active molecules, mainly exhibiting logP values higher than 3. They include antineoplastics (e.g., doxorubicin [4], paclitaxel [5, 6], docetaxel [7, 8], methotrexate [9], triptolide [6], cucurbitacin [10], and sorafenib [11]), antiretrovirals (e.g., efavirenz [12] and

nevirapine [13]), immune suppressants (mycophenolate [14]), anti-inflammatories (clobetasol [15], fluticasone propionate [16], dexamethasone [17, 18], and diclofenac [19]), antimicrobial and antifungal agents (polymyxin B [20], amphotericin B [21], itraconazole [22], and linezolid [23]), antihyperlipidemics (fenofibrate [24, 25]), anesthetics (tetracaine [26] and ketamine [27]), antihypertensives (nimodipine [28] and atenolol [29]), vitamins or their precursors (β-carotene [30] and vitamin E [31]), and antioxidants (quercetin [14, 32]). Likewise, although in a much smaller number, hydrophilic active molecules such alendronate [33], N-acetylcysteine [34], and calcein [35], have been investigated. Moreover, natural extracts such as Brazilian red propolis extract [36] and essential oils [37] have also been incorporated into polymeric nanoparticles.

comprehensive view about the nanoprecipitation as a technique to prepare nanocarriers and its potentialities for developing innovative pharmaceutical

*Nanoprecipitation: Applications for Entrapping Active Molecules of Interest in Pharmaceutics*

**2. Physicochemical fundamentals of the nanoprecipitation technique**

form the nanoparticle because of its amphiphilic nature [49].

To prepare nanoparticles via the nanoprecipitation technique, two miscible solvents are used, one of them being a good solvent (usually an organic solvent as ethanol, isopropanol, or acetone) and the other one acting as a non-solvent for the material that will form the particle (i.e., polymer, lipid, etc.), e.g., water. In general, as shown in **Figure 1**, the nanoprecipitation procedure requires the preparation of an organic phase and a non-solvent phase, frequently named aqueous phase, both guaranteeing the total solubility of all the starting materials. In this sense, the organic phase could contain polymers or solid and liquid lipids, surfactants of low HLB value, and active molecules dissolved in a solvent or mixture of organic solvents. The solubility in the solvent of the active molecule to be entrapped is one of the factors limiting the drug loading of the particles. On its part, the non-solvent phase mainly includes stabilizing agents solubilized in water, which allows the particle formation and the physical stability of the system [2]. Nonetheless, the preparation of particles without stabilizing agents has been reported. In these cases, for example, isoprenoid chains are linked to the active molecule making it easy to

Nanoparticles are spontaneously formed when the organic phase is dropped or added in a one-shot to the aqueous phase. Indeed, nanoprecipitation is a robust process and operational conditions used to prepare the particles do not seem to have a marked influence on the obtained particle size and polydispersity index. On the contrary, the variables linked to the used formulation appear as determinants of the characteristics of the nanosized system, mainly the nature and concentration of the starting materials [47]. This might be closely related to the proposed mechanisms to

*General view of the preparation of polymer, lipid, and hybrid particles by nanoprecipitation summarizing the work conditions commonly reported (PNC: polymeric nanocapsules; PNS: polymeric nanospheres; SLN: solid*

*lipid nanoparticles; HNP: hybrid nanoparticles; RT: room temperature).*

products.

*DOI: http://dx.doi.org/10.5772/intechopen.93338*

**Figure 1.**

**103**

Practical matters as the possibility to use solvents of low toxic potential, the simple procedure, the low energy consumption required, and the feasibility to obtain particles from diverse compositions are also highlighted among the pros of the nanoprecipitation method when carriers at the submicron and nanometric scales are intended [3, 38]. Most of the nanoparticulated drug delivery systems reported as prepared by nanoprecipitation have been developed by using the physicochemical principles governing this technique, primarily those who underpin the precipitation of materials from the mixture of a solvent/non-solvent for the involved material. They include in their majority, polymer, lipid, and hybrid nanoparticles; therefore, this review will be fundamentally focused on them. Nevertheless, some interesting developments of nanoparticles prepared by nanoprecipitation have been reported as well. For example, Arizaga et al. [39] and Villela et al. [40] entrapped magnetic nanoparticles inside polymeric particles, Fan et al. [41] designed spatially controlled release multistage carriers via the complexation of dendrimers with gelatin, and Allen et al. [35] entrapped hydrophobic and hydrophilic active molecules into polymersomes. Likewise, modifications to facilitate the industrial scaling-up of the preparation process have been investigated by Charcosset et al. [42] and D'Oria et al. [43] who developed procedures based on the use of a membrane contactor. On its part, Valente et al. [44] and Tao et al. [45] propose controllable mixing devices such as microfluidic mixer systems that allow continuous and scalable processes for the synthesis of the particles.

Reviews published to date dealing with the nanoprecipitation technique provide valuable information from different standpoints. For example, regarding the role of the obtained particles as drug delivery systems and their applications in medicine, Martínez et al. [46] highlighted their ability for carrying either natural products or actives obtained via chemical synthesis. On the other hand, with respect to the study of nanoprecipitation as a physicochemical process, Mora-Huertas et al. [47] revised the influence of both the formulation and the work conditions used to prepare nanoparticles. In this case, data available in scientific reports supplemented with a systematic study of the nanoprecipitation method led to an approximation to the particle formation mechanisms and identify the factors influencing the particle properties. Recently, Saad and Prud'homme [48] deepened on the physicochemical principles of the nanoparticle formation when amphiphilic block copolymers are used as stabilizing agents (named flash nanoprecipitation). They focused on the key variables determining the nucleation and growth phenomena related to the particle formation, particularly the supersaturation condition, the mixing step, and the used solvents and stabilizing agents.

Based on the above, the present chapter revises the generalities of the nanoprecipitation technique such as the physicochemical aspects involved, some of the starting materials used to obtain polymer, lipid, and hybrid nanoparticles, and their characteristics. Then, the pharmacokinetic behaviors, safety evaluations, and efficacy tests are analyzed. It is our interest to provide readers with a

*Nanoprecipitation: Applications for Entrapping Active Molecules of Interest in Pharmaceutics DOI: http://dx.doi.org/10.5772/intechopen.93338*

comprehensive view about the nanoprecipitation as a technique to prepare nanocarriers and its potentialities for developing innovative pharmaceutical products.
