*2.3. Solubility and Metastable Zone Width Measurements*

Solubility investigations of pure CUR in acetone, acetonitrile, ethanol, methanol and 2-propanol were carried out via the classical isothermal method [41]. To evaluate the impact of the main impurities (DMC and BDMC) on the solubility behavior of CUR, the crude mixture of CURDs no. 2 was used in selected process solvents. Suspensions containing excess of solid CUR and 5 mL solvent were introduced in glass vials. To guarantee efficient mixing of the prepared suspensions, vials were equipped with a magnetic stirrer and sealed. Samples were placed in a thermostatic bath and allowed to equilibrate at constant temperatures between 5 and 70 ◦C for at least 48 h under stirring. Afterwards, samples of equilibrated slurries were withdrawn with a syringe and filtered through a 0.45 μm PTFE filter. Obtained liquid phases were analyzed for solute content by HPLC. To preserve equilibrium conditions for low temperature samples, syringes and filters were precooled before usage. The corresponding wet solid fractions were characterized by XRPD.

**Figure 2.** Analytical HPLC chromatograms of solid standards of BDMC, DMC, CUR and of the crude mixture No. 3 (see Table 1).

Metastable zone width data of pure CUR in selected process solvents were acquired by means of the multiple reactor system Crystal16TM (Avantium Technologies BV, Amsterdam). Suspensions containing known excess amount of solid in solvent were prepared in standard HPLC glass vials, equipped with magnetic stirrers and subjected to a heating step from 5 to 60 ◦C and a subsequent cooling step from 60 to −15 ◦C, both at a moderate rate of 0.1 ◦C/min. Temperatures of a "clear" and "cloud" point representing the respective saturation and nucleation temperatures were obtained via turbidity measurement.

Batch crystallization experiments were conducted in a jacketed 200 mL glass vessel equipped with a Pt-100 resistance thermometer (resolution 0.01 ◦C) connected to a thermostat (RP845, Lauda Proline, Germany) to control the system temperature. A magnetic stirrer was used for agitation.

With respect to the determined solubility behavior of CUR, four process solvents were selected. Consequently, four cooling crystallization processes were derived and conducted. Table 3 gives an overview of the chosen process solvents and the CURD mixtures to be separated. Exact solution composition data (Table 5) and the applied crystallization procedures are presented and discussed in connection with crystallization process design in Sections 3.2 and 3.3.

**Table 3.** Overview of the selected process solvents and the corresponding crude solids.

