RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
The Influence of Feedstock and Process Variables on the Encapsulation of Drug Suspensions by Spray-Drying in Fast Drying Regime: The Case of Novel Antitubercular Drug–Palladium Complex Containing Polymeric Microparticles STEFANO GIOVAGNOLI,1 FRANCESCO PALAZZO,1 ALESSANDRO DI MICHELE,2 AURELIE SCHOUBBEN,1 PAOLO BLASI,1 MAURIZIO RICCI1 1 2
Department of Pharmaceutical Sciences, Universit`a degli Studi di Perugia, Perugia 06123, Italy Department of Physics and Geology, Universit`a degli Studi di Perugia, Perugia 06123, Italy
Received 18 September 2013; revised 11 January 2014; accepted 29 January 2014 Published online 15 February 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23902 ABSTRACT: The purpose of this study was to address the effect of feedstock properties and process variables on the characteristics of antitubercular drug–palladium (Pd) containing poly(lactic) acid (PLA) microparticles (MP) obtained by spray-drying of noncolloidal particle dispersions in fast drying regime. Two different systems were compared: capreomycin–Pd (C–Pd) and ofloxacin–Pd (Ofx–Pd) dispersions in acetonitrile PLA solution. Particle size, dynamic light scattering, differential scanning calorimetry, SEM–energy dispersive X-ray, and spectrophotometric methods were used for MP characterization. C–Pd-loaded MP were optimized preliminarily by experimental design and compared with Ofx–Pd-loaded MP investigated in our previous work. Morphology of feedstock particles had a dominant role in determining MP morphology. The Charlesworth and Marshall theory was used to explain such behavior. The smaller and homogeneous C–Pd microparticulates favored MP inflation and buckling by forming a thick and nonporous shell. A percolation effect was proposed for the larger and irregular Ofx–Pd particles that produced smaller MP with a more porous shell. Increasing feedstock concentration led to higher particle loss. A tentative descriptive scheme of MP formation according to feedstock particle arrangement was proposed. This work suggested that spray-drying of drug dispersions should carefully consider the morphology of feedstock particles as a major parameter C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1255–1268, influencing final MP properties. 2014 Keywords: controlled release; antitubercular drug delivery systems; pulmonary drug delivery; spray-drying; buckling regime
INTRODUCTION Spray-drying is routinely used to produce dry powders for different purposes either at laboratory or industrial scale.1,2 The reason may be explained by ease of automation and process rapidity, which allow standardization of procedures. This reduces variability and improves the technology transfer to large-scale production.3–6 Spray-drying is preferred by other techniques in manufacturing powders for inhalation as it allows for one-step preparation of respirable pure drug dry powders and/or drugloaded particles suitable for pulmonary drug delivery,7 which can be particularly beneficial for the treatment of lung infections, such as Tuberculosis (TB). Because alveolar macrophages are the primary site of TB infection,8 inhalable and low-water-soluble dry powders may be useful to enhance intracellular targeting thus improving the efficacy of TB therapy through drug accumulation in the lungs. This approach can afford 10–100-fold higher drug concentrations in the lungs and 17-fold dose reduction compared with oral administration, limiting the risk of severe systemic side effects.9–11 In light of these considerations, in our previous studies, injectable second-line antitubercular drugs, namely ofloxacin Correspondence to: Stefano Giovagnoli (Telephone: +39-075-5855162; Fax: +39-075-5855163; E-mail:
[email protected]) Journal of Pharmaceutical Sciences, Vol. 103, 1255–1268 (2014)
C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association
(Ofx), kanamycin, and capreomycin (C) were coordinated with palladium (Pd) to produce insoluble complexes.12 Pd has already been used to bind fluoroquinolones and other active molecules providing several active compounds.13–16 Moreover, the Ofx–Pd complex among others12,13 was successfully encapsulated as a dispersion into polymeric microparticles (MP) by spray-drying.17 This process demonstrated a high efficiency in producing MP with good aerodynamic characteristics and high loadings. Nevertheless, beyond instrumental factors, it is well known that the spray-drying process is highly sensitive to the feedstock characteristics.18,19 In fact, flaws have been observed when changes in feedstock properties occur, especially when dispersions rather than solutions are being considered.19,20 Most literature addresses spray-drying of homogenous solutions or colloidal suspensions, which are made of homogeneous particles,21–27 and only a few works deal with irregular noncolloidal drug particles.28,29 This is the case of the second-line antitubercular drug–Pd complexes synthesized in our laboratory12,13 that, because of the insolubility in most organic and aqueous solvents, have to be fed as suspensions. The complex interplay between feedstock properties and spray-drying variables determines final product characteristics by changing the drying profile of the generated droplet. This profile is well addressed in literature and it has been described as a three-step process in which an initial sensible heating step precedes a constant-rate drying period, which is then followed
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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
by a falling-rate drying phase.24,30 During the first heating period, no appreciable evaporation is assumed, whereas in the following step, the droplet shrinks as the solvent evaporates from the surface and the solute or suspended particles within the droplet arrange according to diffusion properties. The actual formation of the particle starts at the beginning of the falling-rate period when the shell begins to thicken because of solidification. At this stage, as the solvent boundary proceeds inward, the forming particle surface can harden or collapse according to the rate difference between solvent evaporation and solute diffusion. Such a balance between the evaporation rate and diffusion is quantified by the Peclet’s number (Pe).24,31–34 When Pe 1, the process is said to be in buckling regime with the formation of hollow or crumpled particles, whereas when Pe 1, a nonbuckling regime leads to more homogeneous spherical particles. Pe is thereby a key factor that can determine the properties of spray-dried particles. In addition to Pe, another important parameter is the atomizing air to liquid feed ratio (ALR) that influences as much as Pe the particle formation process by affecting droplet size and density to a greater extent.6,35 Therefore, these parameters are of crucial importance when suspensions are spray-dried. Dispersed particles have a different behavior compared with solute molecules and their diffusion inside the droplet is driven by their size, shape, and density, beyond of course solvent or solution viscosity.24 Concerning this point, large part of the literature addresses spray-drying of solid dispersions at medium-low buckling conditions and most models for droplet drying are built considering water as main solvent. In this work, we investigated spray-drying of noncolloidal particle dispersions in organic polymer solution of the C–Pd and Ofx–Pd complexes previously synthesized in our laboratory to elucidate the correlation of process performance with feedstock and formulation variables at high buckling regime. For this purpose, the conditions established for Ofx–Pd were used as a starting point and the process was then investigated according to the differences in the feedstock material. In this regard, the set of preparations of Ofx–Pd-loaded MP previously optimized17 were replicated and compared with those obtained for C–Pd to correlate spray-dried MP properties to feedstock material characteristics. Initially, an experimental design was used to establish the optimal conditions for C–Pd-loaded MP preparation.
MATERIALS AND METHODS Materials Capreomycin, Ofx, and K2 PdCl4 were purchased from Sigma– Aldrich (Milan, Italy). Poly DL-lactide (PLA) (molecular weight 29,000 Da, Resomer 203H) was supplied by Boehringer, Ingelheim (Ingelheim, Germany). Acetonitrile was purchased from J.T. Baker (Milan, Italy). All water was Milli-Q grade (Milli-Q System; Millipore, Milan, Italy). Preparation of Drug–Pd Complex MP The drug–Pd complexes were prepared by reacting the drug with K2 PdCl4 in water under mixing at room temperature as reported earlier.12 The complexes were encapsulated into PLA MP by spraydrying of a solid dispersion in acetonitrile polymer solution (total volume 13.5 mL). Spray-drying was performed by using a Giovagnoli et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:1255–1268, 2014
¨ Mini Spray-dryer model B-290 (Buchi, Italy) in co-current mode equipped with a two-fluid nozzle having a 0.7 mm nozzle tip and a 1.5 mm diameter nozzle cap. The aspirator capacity was set to 20 m3 /h. The remaining operating parameters were changed according to the design of experiment presented below. The MP were separated from the drying gas by a high-performance cy¨ clone (Buchi, Italy) providing high yields in collecting particles
