*3.4. Improvement of the Total Yield by Means of Anti-Solvent Addition*

To increase the product yield of the seeded cooling crystallization, it is suitable to conduct anti-solvent addition to the product suspension at the end of the cooling step [39]. In this work, to improve the overall yields of processes 1, 2 and 4 addition of water, 2-propanol and acetonitrile as anti-solvents of CUR in acetone was investigated. The final solvent/anti-solvent ratio was set to 25/75 (wt/wt). The study was conducted using the crude solid no. 1 with the lowest CUR content of 67.2%.

In the first step three equal starting solutions containing 8.5 wt% CUR in acetone were prepared and three identical seeded cooling crystallization processes were carried out as previously described in process no. 1. When the set end temperature of the cooling profile (0 ◦C) was reached, cold anti-solvent (< 0 ◦C) 2-propanol (process 1–2) and acetonitrile (process 1–3) was added to the product suspension, respectively (see Table 7). Afterwards the system was stirred for 3 h at constant 0 ◦C. The addition of water (process 1–1) was carried out at 26 ◦C after introducing CUR seeds to the supersaturated acetone solution. Then the suspension was cooled down to the end temperature 0 ◦C and stirred also for 3 h. Solid-liquid phase separation was performed at the end of each anti-solvent crystallization process. The crystalline products were dried at 40 ◦C and the CUR purity and yield analyzed. To maintain the total product yield and avoid the previously observed dissolution of the filter cake during washing with cold acetone, the washing step was skipped. The results obtained are summarized in Table 7.


**Table 7.** Overview of the results to improve total product yield (η(CUR)) via anti-solvent addition.

In all processes, addition of anti-solvent to the product suspension at the end of the cooling step led to a significant increase of yields. However, the CUR purity in the final crystalline products was noticeably decreased. DMC and in addition low amounts of BDMC (≤1.1%) were present as impurities. In addition to a detrimental effect of abstaining from product washing, an anti-solvent effect on DMC and BDMC cannot be excluded here (even solubility of DMC and BDMC is reported to exceed that of CUR in acetonitrile and isopropanol [34]). However, similar to the cooling crystallization (Table 6), the use of 2-propanol as anti-solvent (process 1–2) provided CUR at highest purity (96.2%) but at significantly lowest yield (36%). Regarding the reduced yield in presence of 2-propanol it can only be presumed at this stage, that, as indicated in polythermal (non-seeded) solubility studies from 2-propanol, an additional metastable (and thus higher soluble) polymorph or solvate phase occurs which causes the respective CUR remaining in the solution phase and thereby reducing the CUR yield in the solid phase.
