*3.1. Selection of Solvents for Crystallization*

To design a crystallization-based purification process, the selection of an appropriate solvent is crucial. The operation parameters for the crystallization process are established based on the specific solubility and nucleation behavior of the target compound in the corresponding solvent.

3.1.1. CUR Solubility in Acetone, Acetonitrile, Methanol, Ethanol and 2-propanol

Acetone, acetonitrile, methanol, ethanol and 2-propanol were selected as possible process solvents because of their low toxicity. CUR solubilities determined in these solvents are shown in Figure 3. As seen CUR solubilities increase with increasing temperature in all solvents. Compared to acetone, CUR is significantly less soluble in the other solvents (less than 1 wt%, except in acetonitrile at 40 ◦C). Hence, acetone was chosen as a suitable solvent for seeded cooling crystallization and acetonitrile, methanol, ethanol and 2-propanol were considered as potential anti-solvents. According to the published very poor solubility of CUR in water (approx. 1.3 <sup>×</sup> <sup>10</sup>−<sup>7</sup> wt% at 25 ◦C) water was also taken into account as anti-solvent without extra solubility studies [20].

**Figure 3.** Solubility behavior of CUR in acetone, acetonitrile, methanol, ethanol and 2-propanol. Symbols represent experimental data, fitted curves just serve as guide to the eyes.

In Figure 4, CUR solid phase XRPD patterns are shown obtained from isothermal equilibration of CUR suspensions (Figure 4a), and by (polythermal) cooling of saturated CUR/solvent mixtures (Figure 4b–f). Measured patterns are compared with references for the three CUR polymorphs derived from single crystal data given in the Cambridge Structural Database (CSD) [42].

Commercial solid standard of CUR, which represents the initial solid for isothermal solubility studies, and all CUR solid phases obtained in equilibrium with saturated solutions in the solvents studied (Figure 4a) perfectly match the pattern of the known CUR polymorph I. XRPD patterns obtained for CUR recrystallized polythermally from acetone and acetonitrile solutions (Figure 4b,c) can be assigned to CUR I as well. CUR phases obtained by cooling of saturated methanol, ethanol and 2-propanol solutions (Figure 4d–f) do not match any shown reference phase, but (except a small missing reflex at 6.8◦ in the ethanol pattern) are identical to each other. Aside from that, their XRPD patterns differ from the CUR I phase only by some additional reflexes in the 2Theta range of 6◦–8◦. One hypothesis explaining this behavior might be incorporation of small amounts of respective alcohol molecules in the crystal structure without changing the structure type. Further, according to the known complex solid phase behavior of CUR [42–48] and BDMC [49,50], also the formation of a new

metastable form of CUR in the three alcohols or a solvate phase from ethanol are possible explanations. Since elucidation of the CUR phase behavior was not the main focus of the present study, this issue has to be verified in future investigations.

**Figure 4.** X-ray powder diffraction (XRPD) patterns of CUR crystalline phases (**a**) obtained from isothermal equilibration of CUR suspensions, and (**b**–**f**) recrystallized by cooling of saturated CUR solutions in acetone (**b**), acetonitrile (**c**), methanol (**d**), ethanol (**e**), 2-propanol (**f**). The topmost diffractogram refers to the CUR solid standard. The three lowermost diffractograms specify the reference crystal structures of CUR polymorphs I-III simulated from CSD single crystal data [42].

With the aim to selectively crystallize pure CUR (form I) from the crude CURD solution and to suppress spontaneous nucleation of undesired DMC and BDMC components, seeding with CUR solid standard (form I) was applied in cooling crystallization experiments.

To evaluate the anti-solvents effect on the CUR solubility in acetone, saturation concentrations of CUR (solid standard) were measured at 30 ◦C in the 50/50 (wt/wt) acetone/anti-solvent mixtures, exemplarily. Figure 5 shows that the obtained solubility data of CUR in the four binary solvent mixtures deviate from the ideal linear behaviors. Moreover, it is seen that the addition of methanol, ethanol and 2-propanol induces a dilution effect rather than the expected supersaturation of the solution. Since the relative dilution effect of ethanol and methanol is larger than that of 2-propanol, they are not considered further for crystallization process design. In contrast, the addition of acetonitrile increases the supersaturation of CUR in acetone. Therefore, a high product yield can be expected. Consequently, the following four process solvents were selected to conduct the seeded cooling crystallization of CUR: pure acetone and acetonitrile as well as 50/50 (wt/wt) mixtures of acetone/2-propanol and acetone/acetonitrile.
