processes Article Systematic and Model-Assisted Process Design for the Extraction and Purification of Artemisinin from Artemisia annua L.—Part IV: Crystallization Maximilian Johannes Huter, Axel Schmidt , Fabian Mestmäcker, Maximilian Sixt and Jochen Strube * Institute for Separation and Process Technology, Clausthal University of Technology, 38678 Clausthal-Zellerfeld, Germany; [email protected] (M.J.H.); [email protected] (A.S.); [email protected] (F.M.); [email protected] (M.S.) * Correspondence: [email protected]; Tel.: +49-5323-72-2355 Received: 30 August 2018; Accepted: 26 September 2018; Published: 2 October 2018 Abstract: In this study, process integration for crystallization of a priori purified Artemisia annua L. is investigated. For this total process, the integration operation boundaries and behavior of the crystals are studied. This is performed focusing on a conceptual process design study for artemisinin, aiming towards the development of a crystallization step under given parameters by process integration. At first, different crystallization systems consisting of ethanol-water or acetone-water mixtures are compared. In subsequent steps, the metastable zone width and the behavior of the crystals regarding agglomeration and breakage are checked. Furthermore, the sensitivities of process variables based on several process parameters are investigated. Additionally, the final process integration of crystallization as a combined purification and isolation step is studied. Keywords: artemisinin; conceptual process design; crystallization 1. Introduction Highly purified substances from natural sources are used to treat various diseases. In addition, the social demand continues to rise [1,2]. To obtain pure substances from plant material, several process steps are necessary. A typical process may include extraction as a capture step, followed by purification steps such as liquid-liquid extraction, chromatography and crystallization [3–6]. The whole study includes a detailed investigation of each process step, a conceptual process design and cost estimation. These aspects are divided into the following five articles: Part 0: Sixt, M.; Strube, J. Systematic and model-assisted evaluation of solvent based- for pressurized hot water extraction for the extraction of Artemisinin from Artemisia annua L. Processes 2017, 5, 86, doi:10.3390/pr5040086 [7]. Part I: Sixt, Schmidt et al. Systematic and model-assisted process design for the extraction and purification of Artemisinin from Artemisia annua L.—Part I: Conceptual process design and cost estimation. Processes 2018, 6, 161, doi:10.3390/pr6090161 [8]. Part II: Schmidt, Sixt et al. Systematic and model-assisted process design for the extraction and purification of Artemisinin from Artemisia annua L.—Part II: Model-based design of agitated and packed columns for multistage extraction and scrubbing. Processes 2018, 6, 179, doi:10.3390/pr6100179 [9]. Part III: Mestmäcker, Schmidt et al. Systematic and model-assisted process design for the extraction and purification of Artemisinin from Artemisia annua L.—Part III: Chromatographic Purification. Processes 2018, 6, 180, doi:10.3390/pr6100180 [10]. Processes 2018, 6, 181; doi:10.3390/pr6100181 www.mdpi.com/journal/processes ProcessesProcesses 2018 2018, 6, 181;, 6, 181;doi: 10.3390/pr6100181doi:10.3390/pr6100181 3 of 173 of 17 becausebecause of the of theinfluences influences of side of side components components on solubilityon solubility and and kinetics kinetics [15 –[17,26,32,42,4315–17,26,32,42,43]. With]. 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Basic process process design design for plant for plant-basedplant-based-based substances substances (LLE, (LLE,(LLE, liquid liquid-liquidliquid-liquid-liquid extraction) extraction)extraction) [8]. [[88].]. FigureFigure 2. Structure 2.2. Structure of artemisinin of artemisinin [8]. [[8].]. 2. Material2. MaterialCrystallization and and Methods Methods is a typical final purification and isolation step preparing for formulation steps of plant-based or semi-synthetical processes, e.g., artemisinin [11–23]. The crystallization step itself is 2.1.affected 2.1Raw. Raw and inandPurified various Purified Material ways, Material based on mechanical and thermodynamic influences, e.g., [24]. The main driving force for crystallization is the solid-liquid equilibrium and, therefore, the solubility of the target Raw Artemisia annua L. and purified artemisinin (CfM Oskar Tropitzsch, Markredwitz, componentRaw Artemisia in a system.annua L. This and solubility purified isartemisinin measurable (CfM viadifferent Oskar Tropitzsch, methods like Markredwitz, the isothermal Germany) are used for this study. The raw plant material is ground to approximately 1 mm with a Germany)excess methodare used orfor the this polythermal study. The raw method, plant material e.g., [25]. is ground