Chemical Engineering Science 60 (2005) 2127 – 2134 www.elsevier.com/locate/ces More efficient preparation of parenteral emulsions or how to improve a pharmaceutical recipe by formulation engineering I. Cuéllar a , J. Bullón a , A.M. Forgarini b , A. Cárdenas a , M.I. Briceño b, ∗ a Laboratory of Mixing, Separation and Chemical Synthesis, University of Los Andes, Mérida 5101, Venezuela b Laboratory FIRP, University of Los Andes, Mérida 5101, Venezuela Received 1 December 2003; received in revised form 20 October 2004; accepted 1 November 2004 Available online 29 January 2005 Abstract Parenteral emulsions are special O/W emulsions used to feed patients whose medical condition makes them unable to eat normally. Therefore, parenteral emulsions must comply with several specifications. One is that the maximum droplet size must be below 5 m in order to avoid the risk of a pulmonary embolism. In this work, we describe the step-by-step procedure followed to simplify a current industrial recipe by applying recently developed principles under the name of formulation engineering. Both hydrodynamic and physicochemical formulation parameters were manipulated to reduce energy input and equipment requirements. The current process consists of two heating steps, three mixing stages and filtering to eliminate droplets larger than 5 m. The mixing stages require first an agitated tank for the making of a coarse dispersion, then a high-speed mixer and last a two-stage homogenizer. Despite the intensive mixing the emulsion does not comply with droplet size specifications and filtering is necessary. Our procedure requires heating once and then two mixing stages, the first to produce a coarse dispersion and the second to refine droplet size in a conventional agitated tank. Further, no filtering is necessary since no droplets larger than 3 m are produced in the mixing tank. The parenteral emulsions resulting of this simplified and less energy intensive process complies with droplet size requirements and are stable over several months.  2004 Elsevier Ltd. All rights reserved. Keywords: Parenteral emulsions; Liquid–liquid mixing; Formulation engineering 1. Introduction Parenteral emulsions are special O/W emulsions used to feed patients whose medical condition makes necessary to provide intravenous nutrition. Parenteral emulsions are also used as potential carriers or controlled delivery systems for poorly water-soluble, oil-soluble drugs (Jeppsson, 1976; Prankerd and Stella, 1990; Yamaguchi et al., 1995). These emulsions consist in essence of a nutritious cocktail, typi- cally 20% of oil that is injected intravenously. Consequently, parenteral emulsions must comply with several specifica- tions such as being bacteriologically pure, physiologically compatible, nutritious and last, but not least, being stable and having a droplet size distribution below 5 m in order to ∗ Corresponding author. E-mail address: mabel@ula.ve (M.I. Briceño). 0009-2509/$ - see front matter  2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ces.2004.11.013 avoid the risk of a pulmonary embolism (Benita and Levy, 1993; Lucks et al., 2000). The typical preparation of parenteral emulsions consists of four major steps. In the first step, the oil and aqueous phases are conditioned by addition to both phases of compo- nents such as the surfactant or emulsifier, glycerol, and other components like vitamins and drugs that are oil or water- soluble. The emulsion is prepared in the second step that involves making oil-in-water coarse dispersions by combin- ing the pre-heated (about 70 ◦ C) aqueous and oil phases. The temperature of this coarse dispersion is then raised up to 70–80 ◦ C and stirred by means of a high-speed me- chanical mixer in order to achieve a fine emulsion with droplet size distribution of 1–5 m. In the third step, the fine emulsion is cooled down below 20 ◦ C and homogenized using a two-stage homogenizer. In the fourth and final step, the emulsion, after pH adjustment, is filtered in order to