Understanding the polymorphism exhibited by organic active-pharmaceutical ingredients (APIs), in particular insight into the relationships between crystal structure and the thermodynamics of polymorph stability, is vital for the production of more stable drugs and better therapeutics, and for the economics of the pharmaceutical industry in general. In this paper, we report a detailed study of the structure-property relationships among the polymorphs of the model API, Sulfamerazine. Detailed experimental characterization using crystallographic determined unit cell and atomic positions (using a synchrotron source) is complemented with computational modelling of the lattice-dynamics and mechanical properties, to study the origin of differences in millability and to investigate the thermodynamics of the phase equilibria. Good agreement is observed between calculated phonon density of states curves and mid-infrared and Raman spectra. The presence of slip planes, evident in the low-frequency lattice vibrations, explains the higher millability of Form I compared to Form II. Energy/volume curves for the three polymorphs, together with the temperature dependence of the thermodynamic free energy computed from the phonon frequencies, explains why Form II converts to Form I at high temperature, whereas Form III is a rare polymorph which is difficult to isolate. Moreover, the combined experimental and theoretical approach employed here should be generally applicable to the study of other systems which exhibit polymorphism.