International Journal of Pharmaceutics 404 (2011) 289–300 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Spray-freeze-drying production of thermally sensitive polymeric nanoparticle aggregates for inhaled drug delivery: Effect of freeze-drying adjuvants Wean Sin Cheow, Mabel Li Ling Ng, Katherine Kho, Kunn Hadinoto ∗ School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459, Singapore article info Article history: Received 10 September 2010 Received in revised form 28 October 2010 Accepted 11 November 2010 Available online 18 November 2010 Keywords: Spray freeze drying Poly(caprolactone) Dry powder inhaler Coalescence Nanoparticles abstract Inhalable dry-powder aggregates of drug-loaded thermally sensitive poly(caprolactone) (PCL) nanopar- ticles are produced using spray-freeze-drying (SFD) as the low melting point of PCL prohibits the use of high-temperature spray-drying. The effects of freeze-drying adjuvant formulation on the particle morphology, aerodynamic diameter, aqueous re-dispersibility, flowability, and production yield are examined using mannitol and poly(vinyl alcohol) (PVA) as the adjuvants. The primary role of the adjuvant is to prevent irreversible nanoparticle coalescences during freeze-drying, thereby the nanoparticle aggre- gates can readily re-disperse into primary nanoparticles in an aqueous environment hence retaining their therapeutic functions. The nanoparticle aggregates produced using either adjuvant exhibit large, porous, and spherical morphologies suitable for dry-powder-inhaler delivery. The nanoparticle aggregates exhibit good flowability and effective aerosolization off the inhaler. The adjuvant selection governs the resultant nanoparticle–adjuvant structures, where PCL nanoparticles are physically dispersed in porous mannitol matrix, whereas PVA are coated onto the nanoparticle surface. Importantly, nanoparticle aggregates pro- duced by SFD exhibit significantly higher aqueous re-dispersibility than those produced by spray-drying, which signifies the suitability of SFD as the method to produce solid-dosage-form of thermally sensi- tive nanoparticles. Overall, using PVA as adjuvant leads to more stable morphology, superior aqueous re-dispersibility, and higher production yield compared to the mannitol formulation. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Dry powder inhaler (DPI) represents an effective pulmonary delivery platform for direct dosing of therapeutic agents to the lungs because of its portability, long shelf-life, and high delivery efficiency. These characteristics of DPI are in contrast to the relative inconvenience (e.g. lengthy treatment time, non-portability) and low delivery efficiency associated with the more conventional neb- ulization delivery platform. The use of nanoparticles as therapeutic carriers in DPI delivery has recently gained significant interest as nano-scale formulations enable the therapeutic agents to evade the lung phagocytic clearance and enhances the dissolution rate of poorly water-soluble drugs (Rogueda and Traini, 2007). Direct inhalation of dry-powder nanoparticles, however, is not plausible because nanoparticles have a strong tendency to agglomerate resulting in difficult physical handling. Furthermore, nanoparticles, with the exception of particles <50 nm in size, are predominantly exhaled from the lung without depositing due to their low aerodynamic diameters (d A )(Rogueda and Traini, 2007). ∗ Corresponding author. Tel.: +65 6514 8381; fax: +65 6794 7553. E-mail address: kunnong@ntu.edu.sg (K. Hadinoto). In this regard, inhaled particles should possess d A defined in Eq. (1) between 1 and 5 m to effectively deposit in the lungs. d A = d G   e  S (1) where d G is the particle geometric diameter,  S = 1 g/cm 3 , and  e is the particle effective density defined as the mass of particles divided by their total volume including the open and closed pores. To facilitate their delivery by inhalation, nanoparticles are typically transformed by spray drying into low-density micro- scale nanoparticle aggregates (i.e. nano-aggregates) with large d G (>5 m) and low  e (≪1 g/cm 3 ) using various pharmaceutical excipients as drying adjuvants (Grenha et al., 2005; Hadinoto and Cheow, 2009; Sham et al., 2004; Sung et al., 2009). The large d G of the nano-aggregates alleviates the problem of particle agglomer- ations resulting in effective aerosolization off the inhaler, without the need for coarse carrier particle inclusion, and improved physi- cal handling. Their low  e , which is owed to either hollow or porous morphologies, ensures their d A to fall within the range suitable for effective lung depositions despite the large d G . Another advantage of this carrier-free DPI formulation is in eliminating the concern of poor liberations of drug particles from carrier particles observed in the conventional DPI formulation. 0378-5173/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2010.11.021