Lactose microparticle formation from finely atomised droplets

Highlights

• Lactose microspheres produced from atomised droplets via antisolvent vapour precipitation.

• Deeper understanding into the microsphere formation mechanism based on new structures obtained.

• Microspheres produced from atomised micron-sized droplets are in the sub-micron scale.

Abstract

The antisolvent vapour precipitation method has been proven to produce uniformly sized lactose microspheres from a single droplet (~1.2 mm diameter) at atmospheric pressure. These types of particles have potential applications in the pharmaceutical industry, especially due to their high solubility and dissolution rate. This article discusses the possibility of using antisolvent vapour precipitation for finely atomised droplets. Microspheres in the sub-micron scale (~0.4 μm diameter) have been produced, much smaller than those obtained from the single droplet method (~1.0 μm diameter). These particles were not affected by ethanol exposure time (up to 60 s) or drying temperature (up to 190 °C), though the structure was related to the absolute humidity of ethanol. We hypothesise a self-emulsified, two-phase system in the droplet could be the responsible for the formation of the porous and bicontinuous structure as an increase in the absolute humidity resulted in a shrinkage phenomenon which led to the microsphere formation.

Introduction

In pharmaceutical applications, the demand for micron-sized particles used in drug delivery systems is increasing. To achieve this, several techniques can be implemented in order to reduce the particle size and distribution. For example, micro-ball or air-jet milling can be used to achieve an average particle size to approximately 5 μm (Saleem and Smyth, 2010). The size distribution of bulk particles is reduced based on the principle that collision between particles imparts stress, resulting in fracture and breakup of the bulk particles into smaller ones (Saleem and Smyth, 2010, Yokoyama and Inoue, 2007). In micro-ball milling, the bulk powder is centrifugally rotated in a chamber with small metal balls which aid in the micronisation process (Bensebaa, 2013). Air jet milling, on the other hand, uses high air velocities to induce fracture on particles when they collide (Chamayou and Dodds, 2007).

Another technique commonly implemented to produce powders with smaller size distribution is spray drying. Widely used in the industry for its large production rates, spray drying involves atomising the feed solution into minute droplets, which increases the surface area to volume ratio. Consequent contact with convective air in the system allows for rapid solvent evaporation in the drying process (Boersen, 1990). The final particle size distribution is highly dependent on feed concentration, feed rate and type of solute (Broadhead et al., 1992). The size of droplets after atomisation directly influences the size of particles produced (Li et al., 2010).

Supercritical antisolvent (SAS) precipitation is also capable of producing monodispersed nanospherical particles. Extensive pilot scale work has been conducted (Reverchon, 1999, Reverchon et al., 2008a, Reverchon et al., 2008b) which shows the reproducibility of the results. SAS precipitation involves the exposure liquid solution to supercritical fluid (usually CO₂) which acts as the antisolvent. The solute is then precipitated in the form of nano-sized particles as it mixes with the supercritical antisolvent fluid (Reverchon, 1999).

While air-jet milling is suitable for producing micron-sized particles, this process requires considerable energy input in order to accelerate the particles to a velocity suitable for fracture (Chamayou and Dodds, 2007, Saravacos and Kostaropoulos, 2002). Moreover, inefficiencies of milling on soft material were also observed; a freezing process is sometimes required in order to reduce the elasticity of the material (Saleem and Smyth, 2010). On the other hand, atomised droplets produced during spray drying have a wide variation of droplet size. Consequently, each droplet would have a different drying profile, which results in variations in particle properties in the same batch (Ilić et al., 2009, Kawakami et al., 2010). Finally, SAS precipitation involves very high operating pressures and hence high equipment cost in order to sustain the process (Reverchon, 1999).

To address these issues, a new technique has recently been developed in order to produce microparticles using antisolvent vapour to precipitate lactose from a single droplet. Using this technique, multiple smooth amorphous microspheres of uniform size (~1.0 μm in diameter) can be produced by exposing a droplet of lactose solution (~1.2 mm in diameter) to a convective mixture of ethanol vapour and nitrogen gas at atmospheric pressure (Mansouri et al., 2012). Long and short dendritic structures have also been observed using this method in addition to the smooth amorphous lactose microspheres (Mansouri et al., 2013). This technique differs from the conventional liquid antisolvent precipitation method; in liquid antisolvent precipitation, the solute (dissolved in solvent) is mixed with the liquid antisolvent in order to induce precipitation, followed by immediate spray drying to minimise the growth of particles resulting in a sub-micron particle size distribution (Hu et al., 2011).

Instead, antisolvent vapour precipitation involves exposing the solution to a vapour form of the antisolvent rather than mixing two liquids. Each droplet produces multiple particles due to the diffusion of antisolvent into the drop. While this single droplet drying technique mimics the convective drying process that occurs during spray drying, the drying time scale was several magnitudes larger than an actual spray dryer (approximately 30 minutes) (Mansouri et al., 2012). Relatively large droplets were used in the single droplet drying technique, at approximately 1.2 mm in diameter, which would explain the long drying time. Droplets produced by atomisers in actual spray-drying processes are usually in the range of tens or hundreds of microns and take less time to dry (Wendel and Celik, 2005).

In this article, for the first time, we will attempt to ‘scale down’ the antisolvent vapour precipitation approach by using atomised droplets to better mimic convective drying processes within a spray dryer. Using lactose as the solute, water as the solvent, and ethanol as the antisolvent, the effect of reducing the average droplet size by several magnitudes on the final particle size distribution will be investigated in this study. The absolute humidity of the ethanol vapour, exposure time and drying temperature, were also varied in an attempt to further understand how these variables affect the formation of the lactose microspheres.