Co-crystal phase diagram determination by the solution addition method

Multicomponent crystals such as co-crystals, salts, and solid solutions can be used to modify physical properties of active pharmaceutical ingredients. Phase diagrams of such multicomponent crystals are essential for crystallization process development, especially in the case where multiple solid phases may coexist. However, additional components and solid phases make phase diagrams more complex and their determination more time consuming. We propose to accelerate this process by identifying the eutectic points and constructing the rest of the phase diagram using thermodynamic models, informed by further measurements, if necessary. In this work, a novel solution addition method is proposed for determining the eutectic points in a co-crystal system. This method implements gradual compositional changes to traverse various regions of the phase diagram. Phase boundaries are determined by monitoring changes in the liquid phase (UV–vis) and solid phase (Raman), and eutectic points are obtained from intersection of phase boundaries. The results from solution addition are compared to those of an equilibration method, which combines gravimetry, XRPD, and NMR to identify the eutectic solution composition starting from a composition in the three-phase region of a co-crystal phase diagram. Both methods were able to locate all eutectic points, allowing construction of the ternary phase diagrams of benzoic acid and isonicotinamide in ethanol.