Thermodynamics and crystallization kinetics

Thermodynamics and crystallization kinetics

Goals within this topic are to gain a deeper understanding of the complex phase behavior of substances and substance/solvent systems, the related crystallization kinetics and its consequences on separation process design. In this connection also development of improved measurement techniques and rationalization of process design is considered as important.

Solubilities in multi-component mixtures and solid phase behavior

Solid-liquid equilibria (SLE), i.e. equilibria between solid and liquid phases, are the thermodynamic foundation of crystallization processes and therefore their knowledge of essential importance for crystallization process design [1]. Usually on the basis of the corresponding melt phase equilibria of a system of interest, we study solubilities of this substance system as initial point for separation process design. Examples investigated in the last years originate from pharmaceutical, food and agrochemical sectors, as e.g. the resolution of chiral systems [e.g. 2, 3] or the isolation of certain target compounds from multi-component mixtures based on plant extracts [e.g. 4, 5, 6].

Figure 1 illustrates the ternary solubility phase diagram of the (R)-/(S)-mefenpyr-diethyl enantiomers (an agrochemical) in a 76/24 (w/w) ethanol/water mixture as solvent. The enantiomers form a racemic compound in the solid state and the SLE in the ternary system are overlaid by a distinct miscibility gap in the liquid state [3].

Figure 2 shows solubility studies performed for isolation of artemisinin from a multi-component reaction mixture. Artemisinin and its derivatives are effective antimalarial drugs. The related investigations were carried out within a broader study directed on recovery of artemisinin as target compound from a complex semi-synthetic reaction mixture using continuous chromatography and crystallization. In this frame solubilities were measured in differently composed solvent mixtures and in presence of impurities [4].

Figure 1: Ternary solubility phase diagram of the (R)-/(S)-mefenpyr-diethyl enantiomers in a 76/24 (w/w) ethanol/water mixture [3]

Figure 2: Artemisinin solubility curves in different toluene/ethanol solvent compositions and in presence of impurities for the 20/80 toluene/ethanol case (red curve) [4]

Solid state forms of Active Pharmaceutical Ingredients (APIs) comprise polymorphs, solvates, salts, co-crystals (binary compounds), solid solutions and amorphous forms. These different phases show diverse properties, such as solubility, dissolution rate and bioavailability. New solid state forms can thus significantly improve the chemical and physical properties of APIs.

Solvates, for example, may be used as optional solid forms of APIs, as precursors of particular desired polymorphs and for purification via the property of solvate formation. An example compound studied in our group is Bis(demethoxy)curcumin (BDMC), one of the main components of Curcuminoids, which can be found in the roots of turmeric spice Curcuma longa. Curcuminoids exhibit various medicinal activities, such as anti-inflammatory, antioxidant and anticancer effects. Within a comprehensive study multiple solvates were identified and characterized [7].

In close collaboration with Prof. E. Kotelnikovas group at St. Petersburg University further projects are concerned with studying the formation and occurrence of solid solutions and non-stoichiometric binary compounds in chiral systems aimed at a deeper understanding of its origins and potential future applications [e.g. 8-11].

Crystallization kinetics

Thermodynamics define the final state of a certain system, while the kinetics provide the pathway to this state, which is essential for process design. In crystallization, mostly growth, nucleation and dissolution kinetics are of interest, which can be measured with various methods, e.g. in single crystal growth cells or directly in the reactor of interest. Observing one crystal surrounded by supersaturated mother liquor with a microscope gives two-dimensional information on the evolution of the crystal shape. Hence, the effect of different additives on the specific face-related growth rates can be evaluated efficiently and fast in a qualitative way. However, a certain number of individuals have to be observed to achieve statistical significance of the measures if the extracted growth kinetics shall be used afterward for process predictions [12].

Thus, it can be beneficial to investigate a collective of crystals directly under process conditions to decrease the necessary time of kinetic measurements. A measurement technique applicable for this purpose is online microscopy, which has recently proven to be reliable. Suspension is withdrawn from the crystallizer for its application and fed continuously, unclassified, to a flow-through cell where it is observed with appropriate optics, light sources and a camera (Figure 3). The generated pictures yield, after several image processing algorithms, the evolution of the whole crystal bulk-phase (Figure 4). Together with information on the mother liquor, i.e. temperature, composition and/ or concentration, kinetic parameters of appropriate mathematical approaches are estimated, which can subsequently be applied with population balance equations to design, visualize or optimize crystallization processes [13-16]. Exemplarily, Figure 5 shows growth rates determined for L-asparagine monohydrate crystals from racemic and pure L-asparagine solutions [16].

Figure 3: Process scheme for the quantification of crystallization kinetics applying a developed shortcut method [16]

Figure 4: Core idea of the shortcut method: evolution of a seeded cooling crystallization together with the evaluation of the growth and dissolution rate of the seed crystal fraction [15]

Figure 5: Comparison of growth kinetics of L-asparagine monohydrate seed crystals from racemic and pure L-asparagine solutions [16]

References

[1] Lorenz, H. (2013), Solubility and Solution Equilibria in Crystallization. In: Beckmann, W. (Ed.): Crystallization: Basic Concepts and Industrial Applications, Wiley-VCH, Weinheim, pp. 35–74
[2] Kort, A.-K., Lorenz, H., Seidel-Morgenstern, A. (2016), Chirality 28, pp. 514-520
[3] Kort, A.-K., Lorenz, H., Seidel-Morgenstern, A. (2017), J. Chem. Eng. Data 62, pp. 4411-4418
[4] Horváth, Z., Horosanskaia, E., Lee, J. W., Lorenz, H., Gilmore, K., Seeberger, P. H., Seidel-Morgenstern, A. (2015), Org. Process Res. Dev. 19, pp. 624-634
[5] Horosanskaia, E., Nguyen, T. M., Dinh, V. T., Seidel-Morgenstern, A., Lorenz, H. (2017), Org. Process Res. Dev. 21, pp. 1769-1778
[6] Horosanskaia, E., Lorenz, H., Seidel-Morgenstern, A., Minh Tan, N., Dinh Tien, V.: Batch and semi-continuous isolation of highly pure Rutin from rutin extract of plant Sophora Japonica. VN-patent application No.1-2016-01852 (20. 05. 2016)
[7] Yuan, L. Lorenz, H. (2018), Crystals 8, DOI: 10.3390/cryst8110407
[8] Kotelnikova, E. N., Isakov, A. I., Lorenz, H. (2018), CrystEngComm 20, pp. 2562-2572
[9] Kotelnikova, E. N., Isakov, A. I., Lorenz, H. (2017), CrystEngComm 19, pp. 1851-1869
[10] Isakov, A. I., Kotelnikova, E. N., Münzberg, S., Bocharov, S. N., Lorenz, H. (2016), Cryst. Growth Des. 16, pp. 2653-2661
[11] Taratin, N., Lorenz, H., Binev, D., Seidel-Morgenstern, A., Kotelnikova, E. (2015), Cryst. Growth Des. 15, pp. 137-144
[12] Henniges, M., Hosseini, S.A., Lorenz, H., Thévenin, D., Seidel-Morgenstern, A. (2017), Towards predictive numerical models for single crystal growth: validation of the velocity field. Proceedings 24th Int. Workshop on Industrial Crystallization (BIWIC 2017), Dortmund (Germany), pp. 105-110
[13] Temmel, E., Eisenschmidt, H., Lorenz, H, Sundmacher, K., Seidel-Morgenstern, A. (2016), Cryst. Growth Des. 16, pp. 6743-6755
[14] Temmel, E., Eicke, M., Lorenz, H., Seidel-Morgenstern, A. (2016), Cryst. Growth Des. 16, pp. 6756-6768
[15] Temmel, E. (2016), Ph.D. thesis: Design of continuous crystallization processes. Shaker Verlag, Aachen
[16] Temmel, E., Gänsch, J., Lorenz, H., Seidel-Morgenstern, A. (2018), Cryst. Growth Des. 18, DOI: 10.1021/acs.cgd.8b01322
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