Evaluation of the difficulty of crystallization of organic compounds using the critical supersaturation ratio (Sc)

• Critical supersaturation ratio (Sc) to remove kinetic effect from the S was defined.
• The Sc at 298 K (Sc298) of pharmaceutical compounds were compared.
• The value of lnSc298 reflected compound structure property and solvent species.
• The proposed Sc is optimal index to compare the difficulty of crystallization.

In the case of solvent selection, supersolubility is an index for improving crystallization behavior. However, supersolubility is affected by kinetic factors such as the cooling rate. An index for suitable solvent selection is needed. The supersaturation ratio (S) is one of the operation design indices of controlling crystallization behavior such as supersolubility. The S at 298 K (S298) of the pharmaceutical compounds theophylline, noscapine, clotrimazole, indomethacin, carbamazepine, naproxene and tolbutamide were measured in ethanol using a polythermal method. If the compound had a large lnS298, the cooling rate strongly affected the temperature of the cloud point in the cooling crystallization method. In order to estimate the crystallization behavior without the cooling rate effect, the critical supersaturation ratio (Sc) was proposed. Sc at 298 K (Sc298) was calculated from dissolution/cloud points at 0 K/min extrapolated from that of several heating/cooling rates to remove the kinetic effects on S. The lnSc298 values of theophylline, noscapine and clotrimazole were estimated in acetonitrile, methyl ethyl ketone, tetrahydrofuran, ethyl acetate, methanol, ethanol and isopropanol. The lnSc298 value of clotrimazole was the largest in all solvents. The results showed that lnSc298 was a simple index which could be used to evaluate the crystallization behavior resulting from the interaction between the solvent and the compound. In conclusion, the proposed lnSc298 should be useful for comparing the difficulty of crystallization which indicates how we should obtain desired crystals within a certain finite time period for development API in the manufacturing field without considering the effect of the heating/cooling rate.