Adami, Renata

Campardelli, Roberta

E., Oleandro

Reverchon, Ernesto

CAMPARDELLI, ROBERTA

E. OLEANDRO

ADAMI, RENATA

REVERCHON, Ernesto

Archivio istituzionale della ricerca - Università di Genova

Supercritical Assisted Injection in a Liquid Antisolvent to produce micro and nanoparticles

Archivio della Ricerca - Università di Salerno

Tenth Conference on Supercritical Fluids and Their Applications Naples, Italy, April 29-May 06, 2013– Eds. E. Reverchon, I. De Marco  193 Supercritical Assisted Injection in a Liquid Antisolvent to produce micro and nanoparticles  R. Campardelli1, E. Oleandro1, R. Adami1, E. Reverchon1*  1Department of Industrial Engineering, University of Salerno. Via Ponte Don Melillo, 84084, Fisciano-Salerno, Italy *tel. +39089964116, fax: +39089964057, ereverchon@unisa.it   Supercritical Assisted Injection in Liquid Antisolvent (SAILA) is proposed to produce stable water suspensions of micro- and nanoparticles of controlled size and distribution. The process is based on the solubilization of controlled quantities of supercritical CO2 in liquid solutions containing a solid solute and on the subsequent direct injection of the ternary solution through a nozzle in an antisolvent solution. In this work SAILA has been successfully tested using some different kinds of compounds: polymers and pharmaceutical compounds, using acetone as liquid solvent and water as antisolvent. Examples of the results of this technique are nanometric and micrometric suspensions of stearic acid, β-carotene, ketoprofene, beclomethasone, budesonide, aliamide. Different particle morphologies have been obtained. A systematic analysis of the influence of the concentration of the liquid solution, and CO2 molar fraction of the expanded liquid on the particle size and distribution of SAILA-produced suspensions is also proposed.  INTRODUCTION It has been reported that approximately 40% of drugs in pharmaceutical interest fall in the Biopharmaceutics Class II (low solubility–high permeability), and Class IV (low solubility–low permeability) category. The bioavailability of drugs in these classes is limited due to their low solubility and dissolution rate. Various drug formulation strategies have been extensively studied to improve the dissolution rates of these drugs, over the past few decades. One of the newest formulation strategies is to prepare nanoparticles/microparticles of these drugs. Indeed, the decrease in particle size increases the surface area to volume ratio which increases the solubility and dissolution rate of poorly water-soluble molecules, and hence bioavailability [1]. The nanoparticles can be produced either by top-down methods or by bottom-up methods [2]. The bottom-up methods in particular, produce fine particles by starting at the atomic level. These methods give better control over particle properties such as, size, morphology and crystallinity as compared to top-down methods. These processes are one-step processes but have disadvantages such as, low yield and degradation of heat sensitive drugs [3].  Supercritical fluid based literature has proposed some processes aimed at the production of nanoparticles of organic compounds, that can be used in several industrial fields [4]. Reverchon and co-workes have recently proposed an innovative technique for the production of stable aqueous nanodispersion  named Supercritical Assisted Injection in Liquid Antisolvent (SAILA). An expanded liquid solution is formed using SC-CO2 and an organic solvent in which a solid solute is also solubilised. Then, the expanded ternary solution is depressurized directly into water (in which a surfactant can be added)  where the solute is not soluble and the organic solvent is miscible; therefore, the water based solution works as a liquid antisolvent.  Operating in this manner, nanoparticles can be generated [5].  Campardelli et al. 194 In this work the SAILA technique has been applied for the precipitation of different kinds of compounds using acetone as liquid solvent and water as antisolvent. A systematic analysis of the influence of the concentration of the liquid solution and CO2 molar fraction of the expanded liquid on the particle size and distribution of SAILA-produced suspensions is also proposed.  MATERIALS AND METHODS  Materials CO2 (99.9%, SON, Naples, Italy), Polysorbate (Tween 80, Aldrich Chemical Co.), Sorbitan monolaurate (Span 20, Aldrich Chemical Co.), Acetone (AC, purity 99.9%, Aldrich Chemical Co.), distilled water, stearic acid, β-carotene, ketoprofene, beclomethasone, budesonide, aliamide (Aldrich Chemical Co.).  Apparatus A schematic representation of the SAILA process layout is reported in Figure 1. It mainly consists of two feed lines, used to deliver the compressed CO2 (A) and the liquid solvent (B) to a mixing vessel (saturator, C). Carbon dioxide is cooled, pumped, preheated and delivered to the saturator (C). The liquid mixture formed by the solvent (in which a solid solute is dissolved), is delivered to the saturator by a membrane pump and is preheated before the inlet to saturator. The saturator is a high-pressure vessel with an internal volume of 0.15 dm3, heated by thin band heaters (E) and is packed with stainless steel perforated saddles with a high specific surface area (D). It provides a large contacting surface and an adequate residence time (3-5 min, depending on the flow rates) for the liquid-gas mixing. Therefore, an efficient, continuous solubilisation of SC-CO2 in the liquid solution is obtained. As a result, they form an expanded liquid, whose position in the vapor-liquid equilibrium diagram (VLE) of the system CO2-organic solvent depends on the conditions of temperature, pressure and on gas to liquid ratio (GLR, here expressed as weight ratio). The solution at the exit of the saturator is injected into the receiving water phase using an orifice that has a diameter of 100 μm. Specifically, the liquid solution is prepared dissolving a known amount of solute (PCL) in acetone. The receiving phase is formed by water in which the solute is not soluble; in this case, it is a water solution containing Tween 80 (0.2% w/w), used as co-surfactant.    Figure 1. Detail of the saturation-injection of the SAILA process apparatus.  Tenth Conference on Supercritical Fluids and Their Applications Naples, Italy, April 29-May 06, 2013– Eds. E. Reverchon, I. De Marco  195  Nanoparticle  morphology and size distributions analysis   Particle size distribution (PSD) of the produced suspensions were determined by dynamic light scattering (DLS) (Zetasizer,  mod. 5000, Malvern Instruments Ltd). Mean size and particles size distribution were measured three times for each sample. Nanoparticle morphology was analysed by FESEM (LEO 1525, Carl Zeiss SMT AG). Samples were prepared by spreading concentrated nanoparticle dispersions over aluminium stubs and drying them at air. The samples were then coated with a gold layer.  RESULTS AND DISCUSSION In processes based on liquid antisolvent, particles precipitate by sovrasaturation produced by the mixing of solvent and antisolvent. The compound to be processed must be soluble in the solvent and non soluble in the antisolvent. Solvent and antisolvent should be completely miscible. SAILA process proposal started from the general consideration that the continuous injection of the expanded liquid in water should be more effective than the injection of an ordinary liquid, since expanded solutions are characterized by a reduced surface tension that, at high gas molar fractions will be near to zero [6]. Therefore, the mixing with a liquid (water) characterized by a high surface tension, could maximize the surface tension difference and largely favour their very fast mixing thus producing small particles. The first set of experiments was performed fixing the temperature (T) in the saturator at 80°C, the CO2 flow rate at 12 gr/min, the acetone solution flow rate at 15 gr/min. Operating in this way it is obtained the gas to liquid ratio GLR=1.  The corresponding CO2 molar fraction can be calculated using the molecular weight of acetone and CO2 (MWAC, MWCO2), as shown in the following equation:   1     𝑋𝐶𝑂2 =𝐺𝐿𝑅𝑀𝑊𝐴𝐶𝑀𝑊𝐶𝑂21 + 𝐺𝐿𝑅𝑀𝑊𝐴𝐶𝑀𝑊𝐶𝑂2 The SAILA operating point obtained for the precipitation experiments reported in Figure 3 is represented in the vapour liquid equilibrium diagram of the binary system CO2-acetone, adapted from the literature, Figure 2. Using an injector of 100 µm diameter a pressure of 80 bar was established in the saturator.    Campardelli et al. 196 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0406080100  P, barX,Y CO2T=80°C Figure 2. Representation of the high pressure VLE of  the system acetone-ScCO2 at 80°C adapted from Sato et al. [7]. The operating point of the experiments reported in Figure 3 is also represented. Different pharmaceutical compounds were processed at these operating conditions.  SAILA process allowed the production of stable particle suspensions for a wide variety of compounds tested. This is an important result, because the direct stabilization in water of hydrophobic compounds is extremely appealing for pharmaceutical industries. Some FESEM images of the particles obtained with the SAILA precipitation experiments are reported in Figure 3. Looking at the FESEM images it is possible to note that also different morphologies and different particle dimensions can be obtained. For example, stearic acid, β-carotene, and ketoprofene precipitated in form of spherical nanometrical particles, instead the formation of crystals have been obtained for other compounds, such as budesonide, beclomethasone, and aliamide.   As stated earlier, particle formation by liquid antisolvent involves mixing of solution–antisolvent streams to generate supersaturation and precipitation of particles. Thus, there are two main time scales associated with it; mixing time (τmix) and precipitation time (τprecipitation), which is also called the induction time; τprecipitation refers to time scale of physical changes incurred during phase shift, which are nucleation and growth. The ratio of τmix to τprecipitation is the dimensionless Damkohler number (Da):   2      𝐷𝑎 =𝜏𝑚𝑖𝑥𝜏𝑝𝑟𝑒𝑐  A value of Da>1, implies a mixing controlled process whereas Da<1 implies that the precipitation step controls the process. Therefore, if the device mixes the solvent and antisolvent streams optimally, the Damkohler value shifts to Da<1, subsequently driving the process to yield ultra-fine particles. The different morphologies obtained with the SAILA process can be explained considering that fixing the mixing time (at constant operating conditions), the different compounds processed, exhibited different precipitation time, i.e. when the precipitation time is larger than the mixing time almost all the sovrasaturation is consumed by nucleation leading to formation of small particles. This is the case of stearic acid, ketoprofene and β-carotene instead when the precipitation time is smaller than the mixing time particles have time to grow, leading to formation of small crystals, such as budesonide, beclomethasone, and amide.  Tenth Conference on Supercritical Fluids and Their Applications Naples, Italy, April 29-May 06, 2013– Eds. E. Reverchon, I. De Marco  197    Stearic Acid Ketoprofene Β-carotene    Budesonide Beclometasone Aliamide  Figure 3. Different compound morphologies processed with the SAILA process  CONCLUSIONS In this work the SAILA process reveals to be a promising technique for the production of stable  water suspensions of poorly water soluble drugs. It is possible to obtain different particles morphologies depending on the crystallization rate of the processed compounds. Spherical particles down to 100 nm have been obtained in some cases, this results is particularly interesting because the nanometric level is difficult to reach when operating with organic compounds.    Campardelli et al. 198 REFERENCES [1] A.A. Thorat, S.V. Dalvi, Chemical Engineering Journal, 181, 2012, p. 1. [2] V.B. Patravale, A.A. Date, R.M. Kulkarni, J Pharm Pharmacol, 56, 2004, p. 827. [3] A. Chow, H. Tong, P. Chattopadhyay, B. Shekunov, Pharmaceutical Research, 24, 2007, p. 411. [4] E. Reverchon, R. Adami, S. Cardea, G. Della Porta, J Supercrit Fluid, 47, 2009, p. 484. [5] R. Campardelli, R. Adami, G. Della Porta, E. Reverchon, , Chemical Engineering Journal, 192, 2012, p. 246. [6] G. Brunner, Gas extraction, New York, 1994. [7] Y. Sato, N. Hosaka, K. Yamamoto, H. Inomata, Fluid Phase Equilibr, 296, 2010, p. 25.   

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Supercritical Assisted Injection in a Liquid Antisolvent to produce micro and nanoparticles

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