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 Δtrs 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.

Avant Garde Materials Simulation Alte Str 2 Merzhausen 79249 Germany

Centro de Química Estrutural Institute of Molecular Sciences Departamento de Química e Bioquímica Faculdade de Ciências Universidade de Lisboa 1749 016 Lisboa Portugal

Christian Doppler Laboratory for Advanced Crystal Engineering Strategies in Drug Development Institute of Pharmacy University of Innsbruck 6020 Innsbruck Austria

Department of Chemical Engineering University College London London WC1E 7JE U K

Department of Chemistry University College London 20 Gordon St London WC1H 0AJ U K

Department of Chemistry University of Graz Heinrichstrassse 28 Graz 8010 Austria

Department of Chemistry Via Pietro Giuria 7 10125 Turin Italy

Department of Physical Chemistry University of Chemistry and Technology Prague Technická 5 CZ 166 28 Prague 6 Czech Republic

Excelsus Structural Solutions Parkstrasse 1 5234 Villigen Switzerland

Faculty of Chemistry University of Warsaw Pasteura 1 02 093 Warsaw Poland

GSK Medicines Research Centre Gunnels Wood Road Stevenage Hertfordshire SG1 2NY U K

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague 6 160 00 Czech Republic

Jagiellonian University Faculty of Chemistry Gronostajowa 2 30 387 Krakow Poland

LAQV REQUIMTE Departamento de Ciências Químicas Faculdade de Farmácia Universidade do Porto Rua de Jorge Viterbo Ferreira 228 4050 313 Porto Portugal

Radboud University Nijmegen Institute for Molecules and Materials Department of Solid State Chemistry Heyendaalseweg 135 6525 AJ Nijmegen The Netherlands

Ruđer Bošković Institute Bijenička Cesta 54 10000 Zagreb Croatia

The Cambridge Crystallographic Data Centre 12 Union Road Cambridge CB2 1EZ U K

University of Innsbruck Institute of Pharmacy Pharmaceutical Technology Josef Moeller Haus Innrain 52c A 6020 Innsbruck Austria

University of Rouen Normandy Normandy University SMS laboratory 76000 Rouen France

XtalPi Inc 3F 2 Hongliu Rd Futian District Shenzhen 518038 China

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