Drowning-out crystallization of L-proline: Effect of anti-solvent composition and processing parameters on crystal size and shape Woochan Hyung a , Yehoon Kim a,c , Chan-Hwa Chung b , Seungjoo Haam a, ⁎ a Department of Chemical Engineering, Yonsei University, Seoul 120-749, South Korea b Department of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, South Korea c Chemicals & Polymers Research and Development, LG Chem Research Park, Daejeon, 305-380, Korea Received 28 March 2006; received in revised form 2 November 2007; accepted 11 November 2007 Available online 17 November 2007 Abstract Crystallization of L-proline was investigated using a drowning-out method. Due to the high water and alcohol solubility of L-proline, the recovery of an L-proline product by precipitation using the drowning-out method required suitable anti-solvents selected from immiscibility and solubility studies. Through past experience, acetone and NMP were carefully chosen for analogy and solubility tests in pure anti-solvent. Although phase separation occurred in acetone, ultrasound was used to mix the two immiscible phases and generate fine emulsion droplets. L-proline crystals were obtained using NMP with a general drowning-out method. A spherical agglomerate of L-proline was also obtained using acetone by emulsion solvent diffusion methods. The ultrasound power controlled the agglomerate sizes, and the agglomerate surface transformed from amorphous to crystalline as the residence time increased. Alternatively, when NMP was used as an anti-solvent, L-proline monocrystals with needle type morphology were produced. © 2007 Elsevier B.V. All rights reserved. Keywords: L-proline; Drowning-out; Anti-solvent; Agglomeration; Transformation; Ultrasound 1. Introduction Drowning-out crystallization is widely used for the separa- tion of pharmaceutical products and biomaterials in industrial processes [1,2]. In drowning-out crystallization, supersaturation is generated by adding an anti-solvent, which reduces the solubility of the solute. This method is used for highly soluble materials rather than evaporative or cooling crystallization, which have weak solubility temperature dependence [3]. In particular, it is also suitable for the separation of heat labile material because crystallization can occur at a lower tempera- ture. The use of an anti-solvent to precipitate amino acids is quite common. The effect of operating conditions on crystal size and purity has been extensively studied for the production of various amino acids using drowning-out crystallization [4]. Additionally, complex amino acids [5–7] and the precipitation of proteins such as enzymes [8] have also been investigated. Drowning-out crystallization can also be used to produce spherical agglomerates for improved processability, such as mixing, filling, and tabletting characteristics, and the bioavailability of pharmaceuticals [9]. Although small crystal sizes (b 10 μm) are often needed in the biomaterial or pharmaceutical industry due to their high bioavailability or dissolution kinetics, downstream processes such as filtration, handling, and storage may be difficult. Therefore, the pro- duction of spherical agglomerates of pharmaceutical com- pound crystals has drawn great attention. In the spherical agglomeration process, crystallization, agglomeration, and spheronization can be performed simultaneously. To this end, the selection of an anti-solvent is important to agglomerate the precipitated crystals, especially when a binding solvent is not used [10]. In this study, the drowning-out method was performed to crystallize L-proline. Pure L-proline is an amino acid that has Available online at www.sciencedirect.com Powder Technology 186 (2008) 137 – 144 www.elsevier.com/locate/powtec ⁎ Corresponding author. Tel.: +82 2 2123 2751; fax: +82 2 312 6401. E-mail address: haam@yonsei.ac.kr (S. Haam). 0032-5910/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2007.11.007