NANOMEDICINE

Journal of Controlled Release 147 (2010) 304310

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Journal of Controlled Release

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l

Nanoparticles by spray drying using innovative new technology: The Bchi Nano Spray Dryer B-90
Xiang Li a, Nicolas Anton a,, Cordin Arpagaus b, Fabrice Belleteix b, Thierry F. Vandamme a
a Universit de Strasbourg, Facult de Pharmacie, UMR CNRS 7199 Laboratoire de Conception et Application de Molcules Bioactives, quipe de Pharmacie Biogalnique, 74 route du Rhin BP 60024 F-67401 Illkirch Cedex, France b Bchi Labortechnik AG, Meierseggstr. 40, Postfach CH-9230 Flawil 1, Switzerland

a r t i c l e

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a b s t r a c t
Spray drying technology is widely known and used to transform liquids (solutions, emulsions, suspension, slurries, pastes or even melts) into solid powders. Its main applications are found in the food, chemical and materials industries to enhance ingredient conservation, particle properties, powder handling and storage etc. However, spray drying can also be used for specic applications in the formulation of pharmaceuticals for drug delivery (e.g. particles for pulmonary delivery). Bchi is a reference in the development of spray drying technology, notably for laboratory scale devices. This study presents the Nano Spray Dryer B-90, a revolutionary new sprayer developed by Bchi, use of which can lower the size of the produced dried particles by an order of magnitude attaining submicron sizes. In this paper, results are presented with a panel of ve representative polymeric wall materials (arabic gum, whey protein, polyvinyl alcohol, modied starch, and maltodextrin) and the potentials to encapsulate nano-emulsions, or to formulate nano-crystals (e.g. from furosemide) are also shown. 2010 Elsevier B.V. All rights reserved.

Article history: Received 13 May 2010 Accepted 17 July 2010 Available online 24 July 2010 Keywords: Spray drying Bchi Nanoparticle Nano-emulsion Nano-crystals

1. Introduction Nanoparticles are commonly described as solid colloidal particles, ranging in size from 10 nm to 1 m [13]. Nanoparticles used for drug delivery are designed from macromolecular and/or molecular assemblies, in which the active principles such as drugs are dissolved, entrapped, encapsulated, or even adsorbed or attached to the external interface. Nanoparticles can be categorized into two main groups based on their morphology: nanospheres, presenting a homogeneous, matricial structure in which the drugs are uniformly dispersed [4], and nanocapsules, showing a typical core-shell structure. The formulation of nanoparticles involves certain challenges: size control and distribution, morphology, the therapeutic goal of drug delivery, biocompatibility of the polymer and compatibility of the physicochemical properties of the drug. The methods used to produce nanoparticles can be divided into three main groups [2,5]: (i) physicochemical methods e.g. the creation of nanoparticles using preformed polymers and inducing their precipitation by emulsicationsolvent evaporation, diffusion or reverse salting-out (ii) in situ chemical synthesis methods of macromolecules, giving rise for instance to polymerization or

Corresponding author. Tel.: +33(0)3 68 85 42 13; fax: +33(0)3 68 85 43 06. E-mail addresses: xiang.li@etu.unistra.fr (X. Li), nanton@unistra.fr (N. Anton), arpagaus.c@buchi.com (C. Arpagaus), belleteix.f@buchi.com (F. Belleteix), thierry.vandamme@pharma.u-strasbg.fr (T.F. Vandamme). 0168-3659/$ see front matter 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2010.07.113

interfacial polycondensation reactions [4] (iii) mechanical methods e.g. use of high-energy devices like high pressure homogenizers, soniers [2], or high-energy wet mills [3]. The relative interest of using nanoparticulate rather than microparticulate systems in pharmaceutical applications is in their potential to increase the absorption rate, improve bioavailability, enable target drug delivery for cancer therapy and intravenous delivery systems and so forth [3]. This paper will focus on the generation of nanoparticles by mechanical methods, that is to say, the third of the above-mentioned methods. The originality of this study lies in its use of new technology developed by Bchi, the so-called Nano Spray Dryer B-90. This gives rise to a fundamentally new concept in spray drying technology, that of producing submicron particles from a solution. A traditional spray dryer is generally used to transform liquid substances into powders rapidly and efciently. The speed of the process and the consequently short drying time enables the drying of even temperature-sensitive products without degradation [6,7]. This spray drying process is particularly used to improve product conservation in dried solid form. With the development of active compound and emulsion encapsulation used in pharmaceutics, cosmetics and functional food preparation, this method has also been used for encapsulation purposes. The powder thus generated is a matrix system in the form of microparticles (i.e. microspheres [5]), exhibiting a spherical or hollowed morphology depending on the nature of the wall material used and the operational drying conditions such as the inlet temperature, solid concentration, gas

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ow rate or feed rate. The powder samples are generally heterogeneous and amorphous. Overall yields of spray drying on a laboratory scale are limited, reaching around 50% to 70% [8]. The strength of the Bchi Nano Spray Dryer B-90 lies in its vibration mesh spray technology, creating tiny droplets (before evaporation) in a size range of a smaller order of magnitude than in classical spray dryers. This is a revolution in spray drying technology, making it possible to produce powders in the submicron size range with very narrow distributions and high formulation yields [9]. Our aim in this study was to evaluate the potentials and limits of this new spray dryer. Firstly, by determining particle size, distribution, homogeneity, morphology, formulation yields and general aspects of the samples, the inuence of both the wall materials (of polymeric nature) and the different experimental conditions were investigated. The second part of the study focused on the encapsulation of a model lipid dispersion (i.e. a nano-emulsion formulated by a low-energy method [10]) to generate dry submicron particles. The nal part deals with the use of the Nano Spray Dryer B-90 to dry pure active molecules (solubilized in the aqueous or organic phase) in order to produce nano-crystals. Sample characterization was performed by scanning electron microscopy (SEM). 2. Experimental section 2.1. Materials The so-called wall materials used in this work refer to support materials for the spray drying process. The following materials were successively used: arabic gum (kindly provided by CNI Colloides Naturels International, Rouen, France), whey protein (kindly provided by DAVISCO Foods international Inc., USA), polyvinyl alcohol (PVA, from Sigma, Saint-Louis, USA), and Cleargum CO 03psy226 and Glucidex IT 12psy226 (which are, respectively, modied starch and maltodextrin with DE 12, kindly donated by Roquette Frres, France). Nonionic surfactants from BASF (Ludwigshafen, Germany) were kindly provided by Laserson (Etampes, France), and used as received. They are Cremophor ELP from BASF (announced by BASF as puried and compatible with the parenteral administration, with HLB around 1214), which are polyoxiethylated-35 castor oil. Furosemide, an active and hydrophobic model molecule for the formulation of nanocrystals, was kindly provided by Solmag (Garbagnate, Italy). Vitamin E acetate, sodium chloride, and acetone were purchased from Sigma, and ultrapure water was obtained using the MilliQpsy226 ltration system (Millipore, Saint-Quentin-en-Yvelines, France). 2.2. Sample preparation 2.2.1. Wall material solutions The different wall material solutions were prepared in ultrapure water a day prior to performing the experiments (to ensure suitable polymer swelling), and at three different concentrations: 0.1 wt.%, 1 wt.% and 10 wt.%. 2.2.2. Nano-emulsion formulation Lipid nano-emulsions were chosen as lipid model suspensions, with controllable size and polydispersity. The chosen size range of nano-emulsions was a few orders of magnitude smaller than the sprayed droplets and dried particles, that is, smaller than 100 nm. Nano-emulsions were formulated according to the low-energy emulsication process published elsewhere [10]. Briey, the nanoemulsion droplets are generated by bringing into contacts two phases: (i) one is composed of oil plus the hydrophilic surfactant totally miscible; and (ii) the second phase is the aqueous one which can be for instance pure water or buffer. Once these two phases are mixed, the hydrophilic species are immediately solubilized by the

aqueous phase inducing the demixtion of the oil (through spinodal decomposition) in the form of nanometric emulsion droplets. Surfactants immediately stabilized the nano-droplets formed. Vitamin E acetate was chosen as a model oily phase (0.09 g), mixed with the nonionic surfactant (0.06 g) and then brought into contact with the aqueous phase (0.35 g), spontaneously generating nano-emulsions. The surfactant oil weight ratio (SOR) was set at 40%. 1 wt.% of wall material aqueous solution was separately prepared and mixed with the nano-emulsion, in order to obtain a ratio of 1 : 4 between the nano-emulsion and the wall material (dry compounds). The size distribution and polydispersity of nanoemulsions were assessed by dynamic light scattering using a Malvern Nano ZS instrument (Malvern, Orsay, France). The HeliumNeon laser (4 mW) operated at 633 nm with the scatter angle xed at 173, and the temperature was maintained at 25C. The polydispersity index (noted PDI) appears merely as a mathematical denition, accounting for the relative error between curve t and experimental values. The PDI discloses the quality of the dispersion, from values lower than 0.1 for suitable measurements and good quality of the colloidal suspensions, to values close to 1 for poor quality samples, which in concrete terms, either do not present droplets sizes in the colloidal range, or exhibit a very high polydispersity. Measurements were performed in triplicate, before and after performing the spray drying process (ltered on 0.45 m in this latter case). 2.2.3. Spray drying of pure low molecular weight materials In order to formulate nano-crystals, different compounds (hydrophilic or not) were tested and spray dried to obtain nanoparticles of pure active ingredients. Sodium chloride nano-crystals were formulated from aqueous solutions at 0.1 wt.% and 1 wt.% concentrations. Furosemide was spray dried at 1.25 wt.% concentration in pure acetone. In this case the Nano Spray Dryer B-90 apparatus was connected to a cooling unit, the Inert Loop B-295, for safe operation of solvents in a closed-mode conguration. Nitrogen was used as an inert gas to prevent an explosive gas mixture. The O2 concentration in the closed loop was kept below 4 vol.%. 2.3. The new Bchi technology: the Nano Spray Dryer B-90 The Nano Spray Dryer B-90 is based on a new spray drying concept. A complete diagram of the apparatus is illustrated in Fig. 1. The drying gas enters the apparatus from the top, heating up to the setting inlet temperature, then ows through the drying chamber, exiting the spray dryer at the bottom outlet, and is ne ltered before

Fig. 1. Schematic of the Nano Spray Dryer B-90.

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leaving the instrument. The inlet temperature, Tin, and outlet temperature, Tout, are respectively measured just after the heating and just before the ne ltering. The liquid sample was fed to the spray head by a pump. As illustrated in the gure, the generation of droplets was based on a piezoelectric driven actuator, vibrating a thin, perforated, and stainless steel membrane in a small spray cap. The membrane (spray mesh) features an array of precise, micron-sized holes (4.0, 5.5 or 7.0 m). The actuator is driven at around 60 kHz, causing the membrane to vibrate, ejecting millions of precisely sized droplets per second with a very narrow distribution. These extremely ne droplets are dried into solid particles which are collected by electrostatic charging and are deected to the collecting electrode. Finally the resulting powder is collected using a rubber spatula. The operating conditions for the experiments were kept constant at: Tin = 100C, feed rates range from 3 to 25 mL/h (depending on the solution viscosity, composition, etc.), the drying gas ow rate = 100 L/ min, and the spray mesh used in this study was the membrane with 4.0 m sized holes. 2.4. Scanning electron microscope (SEM) and size distribution The size and structure of spray dried nanoparticles were evaluated using a scanning electron microscope Philips XL20 (University of Strasbourg, Plateforme de Microscopie lectronique, Institut de Gntique et de Biologie Molculaire et Cellulaire). The specimens were coated with platinum/gold and examined at 20 kV. The particle size distributions were disclosed from the SEM micrographs using a software-assisted method that we developed, whereby only the particle number and their diameter are collected from the raw images (even for these SEM pictures on which the particles appeared as agglomerated, sticked to the carbon support and metalized). Even if particles form aggregates, our method, by isolating each particle from the rest and dening its surface area, allows individual identication, thus disclosing the particle size distribution. A lognormal extrapolation was applied, with a probability density function p of the form f x; ; = explnx 2 = 2 2 = x 2 (where and are the mean and standard deviation), thus allowing a quantitative comparison of the SEM pictures, and hence between the spray dried samples. 3. Results and discussion 3.1. Formulation with pure wall materials This section deals with the impact of the formulation parameters on the resulting properties of the spray dried powders, i.e., the particle size, polydispersity and morphology, which are determined directly from the raw SEM pictures. These so-called formulation parameters are (i) the nature of the wall materials, (ii) the precise location of powder collection on the cylindrical collecting electrode and (iii) the concentration of the wall material solutions before spray drying. As mentioned in Section 2.1, a representative range of ve different wall materials were spray dried; arabic gum, whey protein, polyvinyl alcohol, modied starch and maltodextrin. Fig. 2 reports SEM micrographs of spray dried powders made from 1 wt. % of wall material solution. The particle size distributions next to the photographs were directly derived from the SEM pictures. Table 1 summarizes the quantitative values of the size peaks and SD, as well as the formulation yields. The inuence of the sample collection locations in the cylinder-shaped electrode is also highlighted: samples collected from the bottom half of the collecting cylinder (the lower 50% indicated in Fig. 1) are labeled subscript 1 and those from the top half (the top 50% indicated in Fig. 1) are labeled subscript 2. The reason for this comparison lies in the basic law of electrostatic physics, which should inuence

the magnitude of the active electrostatic forces on the particles in function of their size. This could result in the segregation of potential particle size along the cylinder length, and therefore in variations in particle size distribution along the cylinder electrode. The spray dried samples were generally powdery and fragile. The SEM pictures appeared homogeneous, presenting sphericalshaped particles, regardless of the wall materials and collecting locations. Furthermore, the peak maxima were clearly below 1 m. For modied starch, the peak was actually below 500 nm, which, for a spray drying technique is a noteworthy result. Along with the neness of the distribution, this is a very novel result for such technology. Besides these homogeneous global results, signicant differences between the maxima and size distribution standard deviations of the samples are highlighted by the quantitative approach reported in Table 1. The comparison demonstrates three main points: (i) the values of the peak size and SD of the bottom part (for reference, this part should normally have smaller particles and a narrower distribution than the top part) (ii) variation of the particle size between the top and the bottom part, and (iii) variation of the SD between the top and the bottom part. The samples of arabic gum (a1) and (a2) showed similar maxima of 565 and 581 nm respectively. The difference was more apparent in the peak widths, with a standard deviation of 287 nm for the bottom part and 363 nm for the top part of the collecting cylinder. This result indicates that bigger particles are more rapidly trapped by the high voltage collection system than smaller ones, resulting in a particle segregation effect over the cylinder length. This phenomenon is further intensied by the surface charge density of the macromolecules, as conrmed by the second example with maltodextrin, a neutral sugar, in which no difference was noted between the two parts of the cylinder. Indeed, there was no signicant difference between the two collection parts; neither for the maxima (657 and 629 nm) nor for the SD values (459 and 435 nm). Polyvinyl alcohol (c) showed a similar trend to maltodextrin, with a very slight rise of both size maxima (from 673 to 729 nm) and peak width (from 386 to 425 nm), and (d) show the results for modied starch, a clearly charged molecule [11]. Here the segregation effect between the two collection parts was signicantly enhanced. This result corroborates the proposed particle separation idea, given that the maxima increased from 457 to 617 nm and the SD from 289 to 396 nm. The next series of experiments were designed to evaluate the effect of the solid concentration in the sample solution on the spray dried particle size distributions. Representative cases were found for arabic gum and whey protein solutions at 0.1, 1 and 10 wt.% concentrations. The results are presented in Fig. 3 and include the quantitative values of the size maxima and SD. The formulation yields are reported in Table 2. At 0.1 wt.%, outstandingly small particle sizes were achieved: the peaks shifted to lower values of 353 and 421 nm with standard deviations of 107 and 144 nm for arabic gum and whey protein respectively. When the sample concentration was increased to 1 wt.%, the size and polydispersity also increased (see Table 2). Further increase of the concentration to 10 wt.% resulted in an enlargement of the peak width, while the peak location remained roughly unchanged. Nevertheless it resulted in severe changes to the general powder morphology (see Fig. 3). These experiments with pure wall materials illustrate the promising potentials of the Bchi Nano Spray Dryer B-90. The generation of spray dried particles is greatly facilitated, with high fabrication yields and very narrow size distributions, with peaks well below 1 m. Size and distribution depend on the nature of the wall materials, the powder collection location (also inuenced and enhanced by the applied material), and mainly on the sample concentration.

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Fig. 2. SEM micrographs of pure wall materials spray dried particles, the concentration for all samples before spray drying was xed at 1%. (a) arabic gum, (b) maltodextrin, (c) polyvinyl alcohol, and (d) modied starch. The subscripts 1 indicates that the samples were collected from the bottom part of the cylinder, and subscripts 2, from the top part. The respective size distribution is reported for each one of the samples (see Table 1). The scale bars are 10 m.

3.2. Encapsulation of nano-emulsions Low-energy nano-emulsions, i.e. simply formed by spontaneous emulsication, were chosen as a model to investigate the potential of the Nano Spray Dryer B-90 for lipid encapsulation. The oil-in-water nano-emulsion formulation procedure was followed, as described in 2.2.2 The nano-emulsion thus obtained was then mixed with 1 wt.% wall material aqueous solution (at the weight ratio of 1 : 4). In order to

Table 1 Size distribution: values of maxima (curve peaks) and standard deviation of the samples presented in Fig. 2. Formulation yields and representative experimental data are also presented: dried initial mass (mini), collected mass (mcoll), inlet temperature (Tin) and outlet temperature (Tout). Wall materials (a1) (a2) (b1) (b2) (c1) (c2) (d1) (d2) Arabic gum (bottom) Arabic gum (top) Maltodextrin (bottom) Maltodextrin (top) Polyvinyl alcohol (bottom) Polyvinyl alcohol (top) Modied starch (bottom) Modied starch (top) Peak SD Yield (nm) (nm) (%) 565 581 657 629 673 729 457 617 287 363 459 435 386 425 289 396 mini/mcoll (mg) Tin/Tout (C)

g74.7 g43.0 g80.9 g94.5

188.8/141.0 100/4358 541.0/232.8 100/4158 357.2/288.9 100/4257 229.6/216.9 100/4358

facilitate encapsulation with the new spray drying process, the lipid nano-droplets were specically formulated, with a size well below 100 nm (84.9 nm, PDI = 0.117). The nano-emulsion sizes were measured before and after spray drying following a redispersion in a volume of water equivalent to that removed (results presented in Table 3). The emulsion/wall material ratio was adjusted in order to obtain suitable powdery samples after spray drying. The SEM results are reported in Fig. 4, and the quantitative values of the size maxima and SD are summarized in Table 4. According to the data obtained, the Nano Spray Dryer B-90 is obviously able to encapsulate emulsions smaller than 100 nm into separated ( i.e. not aggregated) submicron solid particles. In addition, re-dissolving the spray dried powder in water resulted in a redispersion of the encapsulated nano-emulsions without any signicant degradation and/or size increase. This result demonstrates the capacity of this spray drying process to preserve the integrity of nano-structured systems, a fundamental prerequisite for research in nano-medicine and nano-pharmaceutics. It is also worth noting the importance of the nature of the wall materials used. For instance, when using arabic gum, the PDI dramatically increased (from 0.117 to 0.511). This is attributed to the specic surface active features of the arabic gum and its afnities with the oily components of the emulsion, which can induce droplet occulation and destruction.

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Fig. 3. Inuence of the sample concentration on the powder size distribution. (a) arabic gum, and (b) whey protein. The subscripts 1, 2 and 3 respectively indicate the three different concentrations of the aqueous solution before spray drying: 0.1, 1 and 10 wt.%. The samples were collected at the top part of the collecting cylinder. The respective size distribution is reported for each one of the samples (see Table 2). The scale bars are 10 m.

Comparing the SEM pictures (Fig. 4, and Table 4) of encapsulated lipid emulsion to those obtained with pure wall materials (Fig. 2, Table 1) under identical experimental conditions (i.e. WM concentration xed at 1 wt.% collected in the top part of the electrode), we noted that encapsulated lipid nano-emulsions showed a slight increase in peak size along with a slight decrease in peak width, this however shows a non-negligible impact of the presence of the oil droplets on the generation of the dried particles. With an emulsion/ wall material ratio of 1 : 4, the composition of the particles was estimated to contain 80% of hydrosoluble wall material, 12% of oil or active lipophilic compound (vitamin E acetate in this study), and 8% of nonionic surfactant. We can conclude that the presence of surface active compounds such as lipid nano-droplets and nonionic surfac-

tants do not have a signicant impact on the particle fabrication process. The powders obtained exhibited size distributions with maxima still below the 1 m scale and with a relatively narrow size distribution (compared to the results in Tables 1 and 2). 3.3. Nano-crystals produced by spray drying The fabrication of spray dried submicron particles made from solutions using pure active ingredients, i.e. without so-called wall materials (excipients), is a challenge and is still in abeyance. It is however of prime interest in pharmaceutic and cosmetic formulation. The main advantage of nano-sized API crystals for drug delivery systems is the enhanced physicochemical properties of drug dispersion at the nanometric scale. Two model substances were tested in this study. The rst was simply hydrosoluble salt, NaCl, and the second was furosemide, a low molecular weight active

Table 2 Size distribution: values of maxima (curve peaks) and standard deviation of the samples presented in Fig. 3. Formulation yields and representative experimental data are also presented: dried initial mass (mini), collected mass (mcoll), inlet temperature (Tin) and outlet temperature (Tout). Wall materials (a1) (a2) (a3) (b1) (b2) (b3) 0.1 wt.% 1 wt.% 10 wt.% 0.1 wt.% 1 wt.% 10 wt.% Arabic gum Arabic gum Arabic gum Whey protein Whey protein Whey protein Peak (nm) 353 581 549 421 593 537 SD (nm) 107 363 545 144 374 618 Yield (%) 70.2 74.7 54.0 50.8 76.0 89.4 mini/ mcoll (mg) 60.3/42.3 188.8/141.0 365.4/197.3 54.5/27.7 416.1/316.0 1053.5/941.5 Tin/Tout (C) 100/4260 100/4358 100/4158 100/4156 100/3858 100/4760

Table 3 Nano-emulsion size distribution, before mixing with wall materials (WM), mixed with WM before spray drying, and after spray drying when the dried particles are resolubilized in the same water volume. Wall materials Raw nanoemulsion dh (nm) Arabic gum Modied starch Maltodextrin Whey protein PDI Nano-emulsion + WM Before spray drying dh (nm) 95.49 91.49 83.49 88.54 PDI 0.155 0.229 0.088 0.261 Nano-emulsion + WM After spray drying dh (nm) 105.9 161.5 140.6 110.3 PDI 0.511 0.243 0.167 0.268

84:86

0:117

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Fig. 4. Encapsulation of low-energy nano-emulsions by spray drying. (a) arabic gum; (b) modied starch; (c) maltodextrin; and (d) whey protein. Wall material concentrations of the aqueous solution before spray drying: 1 wt.%; Nano-emulsion and the wall material (dry compounds) weight ratio xed at 1 : 4 (see details in the text). The respective size distribution is reported for each one of the samples (see Table 4). The scale bars are 10 m.

molecule with poor solubility in water, used as a diuretic drug to treat congestive heart failure and edema. The results are presented in Fig. 5, and the values of the size maxima and SD are summarized in Table 5. Spray drying a pure species be it hydrophilic or lipophilic with a low molecular weight, results in homogeneous and powdery samples. In the case of sodium chloride, similar results as in Fig. 3, were achieved; the size distribution was in keeping with the sample concentration, and the narrow peaks shifted from 517 to 993 nm by increasing the solid concentration from 0.1 to 1 wt.%. As previously observed when increasing the WM concentration (Fig. 3 and Table 2), this is typically due to an increase of the substance amount within each droplet formed before drying. The furosemide powder size measured 1.24 m using a 1.25 wt.% concentration, which was still considered to be a noteworthy result. The SEM photograph of furosemide (b) shows the formation of nanometric needle-like crystals (see insert in Fig. 5, two of these crystals, indicated by the arrows, were evaluated at a thickness of 66.9 and 152.0 nm) forming only part of the predominant sphere-shaped crystals constituting the particles. This means that the evaporation of discrete droplets totally controls furosemide crystallization, overriding the free needle-like crystallization of the product. Here again, this novel spray drying technology shows signicant potential in formulating nano-materials and this time without the application of wall materials. Avoiding the use of excipients is a considerable advantage in the vast domain of pharmaceutical formulation. In addition to diluting the samples, wall materials can induce adverse effects. The spray drying experiment described above could constitute an optimized and efcient method of API formulation.

Table 4 Size distribution: values of maxima (curve peaks) and standard deviation of the samples presented in Fig. 4. Wall materials (a) (b) (c) (d) Arabic gum Modied starch Maltodextrin Whey protein Peak (nm) 709 625 773 801 SD (nm) 253 275 352 301 Fig. 5. Powder of pure low molecular weight molecules of (a) a model of water soluble salt (sodium chloride), and (b) of a model of poorly soluble drug (furosemide). (a1) and (a2) respectively refer to concentrations of 0.1 and 1 wt.%, and the concentration of furosemide in (b) is 1.25 wt.%. The star indicates the correspondence with an enlarged detail in picture (b). The respective size distribution is reported for each one of the samples (see Table 5). The scale bars are 10 m.

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Table 5 Size distribution: values of maxima (curve peaks) and standard deviation of the samples presented in Fig. 5. Materials (a1) (a2) (b) 0.1 wt.% 1 wt.% 1.25 wt.% Sodium chloride Sodium chloride Furosemide Peak (nm) 517 993 1245 SD (nm) 182 256 482 Yield (%) 81.1 85.4 69.3

Acknowledgments We are very grateful to Bchi for making it possible to carry out this study with the Nano Spray Dryer B-90. Many thanks for their excellent technical support.

References 4. Conclusion The Bchi Nano Spray Dryer B-90 appears to provide very satisfactory results for the formulation of submicron particles, with relatively high yields (70% to 90%) for small sample amounts (50 mg to 500 mg). Five representative polymeric wall materials (arabic gum, whey protein, polyvinyl alcohol, modied starch and maltodextrin) were spray dried and the resulting size distributions were shown to be mainly below the 1 m scale, attaining sizes as low as ~ 350 nm with a standard deviation of ~100 nm for arabic gum (0.1 wt.% solid concentration), which is a very noteworthy result for spray drying technology. The size and standard deviation depend on the nature of the wall material used, the collection location of the powder samples on the collecting electrode (depending on the chemical structure and intrinsic molecule charge) and mainly on the concentration of the spray dried solution. The preliminary results of encapsulated nano-emulsions and formulated nano-crystals using this novel spray drying technology appear to be of extreme interest for API formulation and offer promising perspectives for new pharmaceutical applications using spray drying.
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