Spray drying formulation of hollow spherical aggregates of silica nanoparticles by experimental design

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Abstract

The present work employs an experimental design methodology to optimize the spray-drying production of micron-size hollow aggregates of biocompatible silica nanoparticles that are aimed to serve as drug delivery vehicles in inhaled photodynamic therapy. To effectively deliver the nanoparticles to the lung, the aerodynamic size (dA) of the nano-aggregates, which is a function of the geometric size (dG) and the degree of hollowness, must fall within a narrow range between 2 and 4 μm. The results indicate that (1) the feed concentration, (2) the feed pH, and (3) the ratio of the gas atomizing flow rate to the feed rate are the three most significant parameters governing the nano-aggregate morphology. Spray drying at a low pH (<7) and at a low feed concentration (<1%, w/w) generally results in nano-aggregates having small geometric and aerodynamic sizes (dA = dG  3 μm) with a relatively monodisperse size distribution. Spray drying at a higher feed concentration produces nano-aggregates having a larger dG but with a multimodal particle size distribution. A trade-off therefore exists between having large dG to improve the aerosolization efficiency and obtaining a uniform particle size distribution to improve the dose uniformity.

Introduction

The use of silica-based particles as a drug delivery vehicle continuously gains more prominence as a result of their attractive physico-chemical properties. In contrast to their crystalline counterpart, amorphous silica particles are biocompatible as reflected in their widespread uses as food additives and medical implants. Moreover, certain silica nanoparticles (e.g. xerogels) have been found to be biodegradable (Li et al., 2007, Radin et al., 2005). In comparison to organic-based drug delivery vehicles (e.g. polymer, liposome), drug-bearing silica particles offer several advantages, which are (1) they are more stable to temperature and pH fluctuations, (2) their morphology can be precisely controlled to manipulate the drug targeting-ability and its release profile, and (3) their surface, just like other metal oxides, is decorated with hydroxyl groups making the silica particles less vulnerable to the opsonization by the body immune system (Barbe et al., 2004).

In particular, silica nanoparticles are being actively researched as a delivery vehicle of photosensitizing anticancer drugs in the photodynamic treatment of skin, esophageal, and lung cancers (Bechet et al., 2008, Brown, 2003, Roy et al., 2003). Attributed to their small size (<50 nm) and hydrophilicity, silica nanoparticles can effectively permeate through leaky tumor vasculatures after which they are naturally excreted from the body through the kidney (Roy et al., 2003). In the photodynamic therapy, nanoparticles loaded with the photosensitizing drug are delivered by an intravenous injection after which the nanoparticles selectively accumulate in the tumor tissue. The tissue is next irradiated with a light source of an appropriate wavelength to excite the photosensitive drug, which in turn transfers its excess energy to oxygen molecules in the surrounding tissue to produce reactive oxygen molecules capable of destroying the cancer cells.

The systemic administration of the photosensitive drug, however, leads to a high drug accumulation in the eyes and skin resulting in a phototoxic side effect in which the patients become highly sensitive to light for 4–6 weeks period (Dillon et al., 1988). Another drawback of the systemic administration is the long time-lag (i.e. 48–72 h) for the nanoparticles to accumulate in the tumor tissue. For lung cancer treatment, inhaled photodynamic therapy represents an attractive alternative delivery route, which eliminates the phototoxic side effect and the long time-lag issues (Baumgartner et al., 1996, Moghissi and Dixon, 2003, Moro-Sibilot and Brambilla, 2003). Nevertheless, direct inhalation of the nanoparticles is not plausible because nanoparticulate aerosols are predominantly exhaled from the lung due to their extremely small inertia.

In inhaled drug delivery, the particle aerodynamic diameter (dA) in Eq. (1) is used to characterize the distance travelled by the inhaled particles in the human respiratory airways. Spherical particles with large dA (>10 μm) tend to deposit in the mouth and throat regions, whereas particles with small dA (<1 μm) remain suspended in the air flow and exhaled from the lung (Heyder et al., 1986). Particles for inhaled drug delivery are therefore designed with dA  2–4 μm to facilitate their deposition in the lung alveolar and bronchial regions.dA=dGρeffρunitywhere dG is the particle geometric size, ρunity is equal to 1 g/cm3, and ρeff is the particle effective density defined as the particle mass divided by its total volume including the open and closed pores.

As nanoparticles possess dA  1 μm due to the small dG, they must be formulated into a micron-scale structure with dA  2–4 μm to facilitate their delivery to the lung by inhalation. One formulation approach is by spray drying the nanoparticulate suspension with pharmaceutical excipients (e.g. lactose, chitosan) to produce micron-size particles with dA  dG  2–4 μm in which the drug-bearing nanoparticles are encapsulated within the excipient particles (Grenha et al., 2005, Sham et al., 2004). The drawback of this formulation approach is that the therapeutic efficacy of the nanoparticles depends on the dissolution rate of the excipient particles. Furthermore, excipient particles in dG  2–4 μm range are typically very cohesive resulting in poor aerosolization efficiency. As a result, the spray-dried particles must be blended with coarser particles (dG > 50 μm) to facilitate their aerosolization.

An alternative formulation approach is to spray dry the nanoparticulate suspension into large hollow spherical nano-aggregates, which disassociate back into the primary nanoparticles in the lung interstitial fluid to perform their therapeutic functions (Hadinoto et al., 2006, Tsapis et al., 2002). The large dG of the nano-aggregates (>5 μm) reduces their tendency to agglomerate resulting in high aerosolization efficiency, whereas the low ρeff attributed to the hollow structure results in geometrically large particles having dA  2–4 μm that is ideal for inhalation delivery. Nevertheless, a significant amount of fine particles (dG  1 μm), which are not hollow, are produced at the spray-drying condition of Hadinoto et al. (2006) as indicated in Fig. 1. The significant presence of the fine particles not only reduces the aerosolization efficiency, but also reduces the dose uniformity resulting in poor therapeutic efficacy.

The physical mechanism behind the hollow spherical nano-aggregate formation is illustrated in Fig. 2. Liquid evaporation from the droplet surface exposes the nanoparticles at the receding liquid–vapor interface to the vapor phase. As the surface energy of a solid–vapor interface is greater than that of a liquid–vapor interface, the nanoparticles migrate toward the droplet centre to minimize their surface energy. A fast convective drying rate in which the liquid evaporation time is shorter than the time needed by the nanoparticles to diffuse back toward the droplet centre is required to produce the hollow morphology. A fast convective drying rate is obtained when the local Peclet number (Pe) in Eq. (2), which signifies the importance of the nanoparticle diffusion time scale (r2/DS) relative to that of the convective drying rate (τD), is significantly larger than unity (Tsapis et al., 2002).Pe=r2τDDSwhere r, τD, and DS are the droplet radius, drying time, and nanoparticle diffusion coefficient, respectively.

As a result of the droplet evaporation, the nanoparticles self-assemble at the interface to form a viscoelastic shell that thickens as the drying progresses. The capillary force generated by the meniscus formed in the gap between the nanoparticles drives the nanoparticles closer to form the aggregates. This attractive capillary force, however, is resisted by the repulsive electrostatic force acting as a stabilizer. The competing interaction between the two forces, which is dictated by the colloidal stability of the nanoparticulate suspension, leads to a shell buckling phenomenon that corresponds to a rheology transformation of the shell from the viscous to the elastic regimes (Tsapis et al., 2005). The shell buckling governs the resulting morphology of the nano-aggregates (e.g. dimpled spherical, toroidal) in which an excessive shell buckling can lead to a shell folding resulting in the formation of irregularly shaped nano-aggregates having a wide range of sizes (Vehring, 2008).

The spray-drying formulation parameters must therefore be systemically determined in order to produce the large hollow spherical nano-aggregates. Building on the work of Hadinoto et al. (2006), the objectives of the present work are (1) to identify the spray-drying formulation parameters that govern the silica nano-aggregate morphology, and (2) to optimize the spray-drying formulation parameters with an aim to improve the particle size distribution of the nano-aggregates. Several studies on particle production by spray drying have primarily identified the drying temperature and the feed rate as the two spray-drying parameters that exhibit the most influence on the resulting particle morphology (Billon et al., 2000, Shur et al., 2008, Stahl et al., 2002). More specifically, the drying gas velocity was found to be the most significant parameter governing the production of silica micro-aggregates in a fluidized bed granulator (Hemati et al., 2003, Saleh et al., 1999). Whether similar results are obtained in the production of silica nano-aggregates are to be examined in the present work.

For silica nanoparticles, a majority of the previous works in nano-aggregate production dealt with the production of non-hollow, but porous, spherical nano-aggregates (Gradon et al., 2004, Iskandar et al., 2001, Iskandar et al., 2003). The porous nano-aggregates were produced by spray pyrolysis in an in-house laminar-flow aerosol reactor that is equipped with an ultrasonic atomizer. In the present work, the silica nano-aggregates are produced using a commercial spray dryer that operates in a turbulent-flow regime and uses a two-fluid flow atomizer, hence its production method is significantly different from the previously tested method. The outcome of the present work will therefore open up a new perspective on the production method of spherical aggregates of silica nanoparticles.

Section snippets

Materials

Colloidal silica Ludox TM-40 (Sigma–Aldrich, USA) in the size range of 20 ± 10 nm is used as the model silica nanoparticles. The Ludox nanoparticles have been studied as potential medical implant coatings (Bumb et al., 2008, Roux et al., 2007), and they have been shown in vivo to be naturally removed from the lung with a half-life of 40–50 days (Lee and Kelly, 1992). The silica nanoparticles are not loaded with the photosensitive drug as the emphasis of the present work is on the nano-aggregate

Identifying significant spray-drying formulation parameters

The sixteen experimental runs of the half-factorial design and their responses are presented in Table 1. The results in Table 1 are the average of the two independent replicates. Preliminary runs are first conducted to establish the feasible range for each formulation parameter. The preliminary runs indicate that the nanoparticulate suspension must be prepared in a Trizma base buffer solution (0.3%, w/w) to maintain the colloidal silica stability in order to produce the hollow spherical

Conclusion

Hollow spherical aggregates of biocompatible silica nanoparticles are manufactured by the spray drying method to be potentially developed as a drug delivery vehicle in inhaled photodynamic therapy. The factorial design approach is employed to determine the spray-drying formulation parameters to produce nano-aggregates having morphology ideal for inhaled drug delivery (i.e. 2 μm < dA < 4 μm, large dG, and monodisperse size distribution). The feed concentration, the feed pH, and the ratio of the gas

Acknowledgment

A financial support from Nanyang Technological University's Start-Up Grant (Grant No. SUG 8/07) is gratefully acknowledged.

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