Co-Crystallization Process of Colchicine Cocrystals and Their Thermodynamic Properties

Abstract

Two structurally similar cocrystals, colchicine/L-malic acid (COL/L-MA) and colchicine/D-tartaric acid (COL/D-TA), were prepared to investigate their co-crystallization behavior via in situ ATR-FTIR spectroscopy. Ternary-phase diagrams combined with a 1:1 solution complexation model revealed a strong complexation effect between the active pharmaceutical ingredient and both co-crystal formers. The conventional calibration strategy was applicable to the COL/L-MA system; however, an alternative calibration method was established for the COL/D-TA system to avoid undesired premature nucleation during spectral calibration. Kinetic analysis indicates that cocrystal formation governs the overall rate of the COL/L-MA process, while dissolution of D-TA constitutes the rate-determining step for COL/D-TA, which originates largely from the solubility difference between the two co-crystal formers. Intriguingly, abnormal apparent concentration rises were detected for both systems, yet they arise from fundamentally different origins: mutual solubilization accounts for the concentration surge in COL/L-MA, whereas the anomaly in the COL/D-TA system stems from complexation-induced spectral enhancement instead of real concentration variation. The proposed model successfully distinguishes these spectral artifacts, allowing credible identification of intensive nucleation events and supporting process-condition optimization. This work offers mechanistic understanding and practical guidance for co-crystallization systems containing structurally similar co-crystal formers.