**1. Introduction**

Today, nanomaterials play one of the most important roles in the research and development of modern pharmaceutics [1–3]. New material processing procedures [4–8], combined with di fferent kinds of raw materials [9–13] and novel innovative strategies for constructing functional products [14–18], are frequently introduced into this application field for providing e fficacious drug delivery and enhancing the therapeutic e ffects of active pharmaceutical ingredients (APIs). Among them, electrohydrodynamic atomization (EHDA) is a popular technique for creating nanoproducts, which mainly includes electrospraying and electrospinning. These new methods explore electrical energy to atomize the working fluid for producing solid products at micro or nano scale [19–23].

The past two decades have witnessed the rapid progress of electrosprayed nanoparticles being utilized as functional products in a wide variety of fields [24–30]. In pharmaceutics, further developments of medicated electrosprayed nanoparticles include creating complex nanostructures (just as its counterpart electrospinning [31–36]), production on large scales, potential clinical applications, and commercial products [37,38]. However, the electro–hydro–dynamic working process is still far from being understood, due to the overlap of several disciplines such as fluid mechanics, electric dynamics, and polymer rheology during the extremely fast drying processes of electrospraying [39,40]. Even a purposeful and conscious manipulation of the electrosprayed nanoparticle's diameter is very hard to realize.

Shown in Figure 1 is a diagram about the single-fluid electrospraying process and the possible experimental parameters that can exert significant influences on the diameters of resultant nanoparticles. An electrospraying apparatus brings together the working fluid and electrostatic energy at the convergen<sup>t</sup> point, i.e., the nozzle of spraying head. Between the two electrodes consisting of spraying head and collector, the working fluids are atomized and solidified into particles within several decades of microseconds. Based on this, all the experimental parameters can be divided into three categories which are concluded in Figure 1. Correspondingly, the resultant nanoparticles' diameter ( *D*) can be a function of working fluid's property ( *w*), operation conditions (*o*), and environmental parameters (*e*), i.e., *D* = *f* (w,o,e).

**Figure 1.** A diagram of the single-fluid electrospraying process and the experimental parameters exerting influence on the diameter of resultant nanoparticle.

During the past several decades, numerous publications have investigated the influence of particular parameters on electrosprayed products. These articles disclosed the process-property relationship for intentionally manipulating the particles' diameters, morphology, and surface smoothness [41–43]. However, there are too many parameters that can exert significant influence on the final products during the electrospraying processes [44,45]. For example, the properties of working fluid include polymer concentration ( *C*), viscosity (η), surface tension (δ), and also conductivity (σ). The operational parameters include the applied voltage ( *V*), the fluid flow rate (*F*), and also the particle collected distance (*L*). The environmental conditions include temperature ( *T*), humidity ( *H*), possible vacuum ( *U*), and sometime with hot air blowing.

Thus, it is di fficult to manipulate the diameter of final nanoparticles accurately through particular experimental parameters. In contrast, the parameters of the electrospraying itself seem to be neglected. Compared with the experimental parameters that can be controlled directly by researchers, very few publications have reported uncontrollable parameters in relation to working processes, such as the

size and angle of a Taylor cone, the length of straight fluid jets, and the spreading angle of the atomization region.

Based on the above-mentioned knowledge, here for the first time, we have investigated the influence of spreading an angle of the atomization region on the diameter of resultant nanoparticles. Meanwhile, the influence of applied voltage on the spreading angle and nanoparticles' diameters, and the size of medicated nanoparticle on the drug fast release performance were also studied. Thus, an example about how to disclose the process-property-performance relationship of medicated nanoparticles prepared by modified coaxial electrospraying is showed. In the experiments, ibuprofen (IBU) and hydroxypropyl methylcellulose (HPMC) were selected as the model drug and polymer matrix, respectively. IBU, a typical nonsteroidal anti-inflammatory drug, is broadly exploited to treat pain, fever and inflammation. However, its poor water solubility always limits its fast action for achieving a desired therapeutic e ffect [46–48]. HPMC is commonly utilized as an excipient in oral tablet, eye drops, and capsule formations. It can be used both as a delaying agen<sup>t</sup> for controlled release, as well as an enhancer to improve the soluble rate of a soluble drug [49,50].

### **2. Materials and Methods**
