BEST-CSP Benchmark Study of Polymorphs I and II of Sulfamerazine and the Perils of Polytype Polymorphs

We report the outcome of an interdisciplinary investigation, by the BEST-CSP network, of the kinetically favored form I and the low-temperature stable form II polymorphs of the drug sulfamerazine (SMZ). Form II can be reproducibly obtained by slurrying in acetonitrile-(MeCN)/water at room temperature, though seeding with form II significantly speeds up the conversion. New structure determinations have been obtained for both forms over a wide temperature range, with both single crystal and powder X-ray diffraction methods. Room temperature FT-IR and solid-state ¹³C NMR spectra are provided. The enantiotropic but practically irreversible crystal-to-crystal transition from form II to form I is observed at temperatures ranging from 150 to 170 °C in various differential scanning calorimetry (DSC) experiments, depending on sample and heating rate. The enthalpy of transition at 150 °C is measured as Δ_trs H _m(II → I) = 3.15 ± 0.12 kJ mol^-1. The differences in the heat capacities mean that the DSC measured enthalpies vary with the onset temperature by about 0.55 kJ mol^-1 over the range of heating rates commonly used in DSC experiments. Attempts to find the solvent-mediated transition temperature were complicated by observing that slurrying experiments in both methanol and MeCN/H₂O above 50 °C produce a new, late-identified polymorph, sulfamerazine form V, which is closely related to form I but with an alternative packing of the double layers, i.e., is a polytype polymorph. Forms I and V are only easily distinguishable by high-quality powder X-ray diffraction. Form V appears to be marginally more stable than form I across the temperature range studied. The experimental data, including heat capacities and thermal expansion rates, are used to test a wide range of assumptions and energy models for calculating free energy differences between these polymorphs, illustrating the challenges in computationally modeling the thermodynamic transition temperature between form I and II. The implications of the discovery of form V on establishing the phase diagram of sulfamerazine are discussed.