Volume 2, Issue 2

May 2015                                                                                By Dr Jane Beh (PrinSus, UNSW Australia)

ARISE – A Novel Micronization Process

(Image Source: A recent work by Kurniawansyah et. al., Inhalable curcumin formulations: micronization and bioassay, Chemical Engineering Journal, 2015 – http://authors.elsevier.com/a/1RB324x7R2BoCB) [1]

Particle engineering of inhalable pharmaceuticals is increasingly attracting the attention of researchers. There are several conventional micronization techniques for production of micron-sized particles that are available such as mechanical milling and grinding, spray drying and freeze drying. High-pressure processes using supercritical fluid (SCF) for particle micronization present distinct advantages over the conventional methods. The unique tuneable properties of SCFs have offered the ability to control particle formation and characteristics. In addition, SCF processing can produce products free from organic solvent residues within a single operation unit and sterile operating environments both of which are key aspects of pharmaceutical processing [1-3].

In most of the SCF micronization processes, micrometric spraying devices such as nozzles are required. Nozzles are used to atomize the solvent phase and enhance the mixing patterns and, hence, improve the mass transfer between the solvent rich phase and the supercritical antisolvent. Nevertheless, the use of nozzles is also a major limitation of SCF micronization processing as it suffers the drawbacks of blockage and premature precipitation, which can lead in turn to lower reproducibility of the particle formation process [4, 5]. Hence, a novel process known as the Atomized Rapid Injection for Solvent Extraction (ARISE) was developed at the Process Intensification and Sustainability Research Centre (which was formerly known as Supercritical Fluids Research Centre) in UNSW Australia by Foster and Sih [5].

The ARISE process is a “bottom up” batch method of micronization which utilises a pressure gradient to deliver an organic solution containing dissolved pharmaceuticals into a vessel of static dense or supercritical carbon dioxide [5]. The atomized rapid injection solvent extraction (ARISE) system is a SCF antisolvent method developed to overcome the scale-up limitations related to the use of atomization nozzles [4]. The rapid mass transfer occurring during the ARISE process induces rapid precipitation in a substantially homogeneous environment, hence favoring the formation of particles with controlled morphologies [1]. The ARISE process has been successfully applied to the micronization of several active pharmaceutical compounds and excipients while overcoming the drawbacks experienced when nozzles are in use [4, 6, 7].

Figure 1 illustrates the schematic diagram of the ARISE process [5]. In an ARISE process, the solute is first dissolved in a suitable organic solvent and the solution is introduced into the injection chamber. The precipitation vessel is then pressurized with CO2 to the desired operating conditions. The pressurised precipitation vessel is allowed to attain equilibration. The injection chamber and back pressure chamber are then pressurised with nitrogen (N2) and then allowed to reach equilibrium. The valve V6 is then opened to allow the organic solution to be instantaneously injected into the precipitation vessel by the pressure difference between the injection chamber and the precipitation vessel. The system is left sitting to reach a stable pressure after the rapid injection. Supercritical CO2 is pumped through the system to remove organic solvent. Products are collected from the precipitation vessel after depressurization [5].


Figure 1: Schematic diagram of the ARISE process – Diagram extracted from [5]

Below are two successful examples from the ARISE studies:

  1. Micronization of insulin (Figure 2) – More details can be found at Foster and Sih, Development of a Novel Precipitation Technique for the Production of Highly Respirable Powders: The Atomized Rapid Injection for Solvent Extraction Process, in: Gas-Expanded Liquids and Near-Critical Media, American Chemical Society, 2009, pp. 309-347ARISEFigure 2: 200mg bovine insulin in 50ml sample bottles (a) lyophilized; (b) ARISE process operated at 90 bar; (c) ARISE process operated at 120 bar; (d) ARISE process operated at 150 bar [5]
  2. Inhalable curcumin formulation individually, and in binary or ternary mixtures with hydroxypropyl-β-cyclodextrin (HPβCD) and PVP (Figure 3) – The ARISE process was modified with the use of Argon as replacement of N2. More details can be found at Kurniawansyah et. al., Inhalable curcumin formulations: micronization and bioassay, Chemical Engineering Journal, 2015 – http://authors.elsevier.com/a/1RB324x7R2BoCBFig 2Figure 3: (a) SEM images of: unprocessed curcumin; (b) ARISE processed curcumin; (c) ARISE processed curcumin-HPβCD; (d) ARISE processed curcumin-PVP; (e) ARISE processed curcumin-PVP-HPβCD; and (f) curcumin-PVP-HPβCD physical mixture [1]

Vieira de Melo et. al. (2014) compared precipitation of levothyroxine sodium by using gas antisolvent (GAS) and ARISE methods. The product recovery from the ARISE process was found higher than from the GAS process. The particle size ranged from 370 nm to 500 nm from GAS processed while the particle size ranged from 360 nm to 1200 nm from ARISE processed. The ARISE process offered easy scalability and higher output than GAS process [6].

Alternative approaches in SCF micronization techniques have been attempted to overcome the typical limitations of the conventional micronization techniques in pharmaceutical processing. Supercritical based technologies are also attractive due to the ease of solvent removal and the reduced number of processing steps involved compared with conventional processes. Unlike the GAS process, the ARISE process offers potential of scalability due to its larger throughput and great degree of process tunability [6]. The implementation of the ARISE process on the production scale for specialty products in general and pharmaceuticals in particular is supported by the higher predictability of product characteristics at different operative scale. It is foreseeable that the utilization of SCF techniques in commercial applications can be achieved with limited risk and within a reduced time frame.



[1] F. Kurniawansyah, H.T.T. Duong, T.D. Luu, R. Mammucari, O. Vittorio, C. Boyer, N. Foster, Inhalable curcumin formulations: Micronization and bioassay, Chemical Engineering Journal, 279 (2015) 799-808.
[2] P. York, Strategies for particle design using supercritical fluid technologies, Pharmaceutical Science & Technology Today, 2 (1999) 430-440.
[3] J. Fages, H. Lochard, J.-J. Letourneau, M. Sauceau, E. Rodier, Particle generation for pharmaceutical applications using supercritical fluid technology, Powder Technology, 141 (2004) 219-226.
[4] N.R. Foster, R. Sih, Development of a novel precipitation technique for the production of highly respirable powders: the atomized rapid injection for solvent extraction process in: K. Hutcheson, A. Scurto, B. Subramaniam (Eds.) Gas Expanded Liquids and Near – Critical Media: Green Chemistry and Engineering, ACS Books Department, Washington DC, 2009, pp. 309-347.
[5] N.R. Foster, R. Sih, Development of a Novel Precipitation Technique for the Production of Highly Respirable Powders: The Atomized Rapid Injection for Solvent Extraction Process, in: Gas-Expanded Liquids and Near-Critical Media, American Chemical Society, 2009, pp. 309-347.
[6] S.A.B.V. de Melo, L.T. Danh, R. Mammucari, N.R. Foster, Dense CO2 antisolvent precipitation of levothyroxine sodium: A comparative study of GAS and ARISE techniques based on morphology and particle size distributions, The Journal of Supercritical Fluids, 93 (2014) 112-120.
[7] F. Kurniawansyah, R. Mammucari, N.R. Foster, Inhalable curcumin formulations by supercritical technology, Powder Technology, (Forthcoming) (2015).


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