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 <sup>13</sup>C 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<sub>trs</sub> <i>H</i> <sub>m</sub>(II → I) = 3.15 ± 0.12 kJ mol<sup>-1</sup>. The differences in the heat capacities mean that the DSC measured enthalpies vary with the onset temperature by about 0.55 kJ mol<sup>-1</sup> 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/H<sub>2</sub>O 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.

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Journal
Crystal Growth & Design
Published
2025-12-12
DOI
https://doi.org/10.1021/acs.cgd.5c01406
Primary Topic
Drug Solubulity and Delivery Systems
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article
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article

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

Mihails Arhangelskis, Marlena Gryl, Sarah L. Price, Carlos E. S. Bernardes et al.
Crystal Growth & Design
Drug Solubulity and Delivery Systems
article

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

Mihails Arhangelskis, Marlena Gryl, Sarah L. Price, Carlos E. S. Bernardes, E. De Ronde, William R. D. Wood, Bruno Mladineo, Y. Zhang, Dejan-Krešimir Buč̌ar, Martin Dračínský, Bartolomeo Civalleri, Lorenzo Donà, Paul Tinnemans, Ivo B. Rietveld, Jonas Nyman, Matteo Salvalaglio, Zhuocen Yang, Johannes Hoja, Reynaldo Marcelino Geronia, Nicolas Couvrat, Vojtěch Štejfa, Anna A. Hoser, Mafalda C. Sarraguça, Michal Fulem, Helena Butkiewicz, Ivor Lončarić, Dzmitry S. Firaha, Joanna Krzeszczakowska, Doris E. Braun, Pamela S. Whitfield, A. Daniel Boese, Ctirad Červinka, Rui Rodrigues, Наталя Гончарова, Alexander List, L. Russo, Guangxu Sun, Erika Bartůňková, Edgar Olehovics, Mattia Raimondo, Jiří Šnajdr
article en

Abstract

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 <sup>13</sup>C 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<sub>trs</sub> <i>H</i> <sub>m</sub>(II → I) = 3.15 ± 0.12 kJ mol<sup>-1</sup>. The differences in the heat capacities mean that the DSC measured enthalpies vary with the onset temperature by about 0.55 kJ mol<sup>-1</sup> 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/H<sub>2</sub>O 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.

Crystal Growth & DesignVol. 26(1)
Jagiellonian University (PL), University of Lisbon (PT), Radboud University Nijmegen (NL), University of Graz (AT), Universidade do Porto (PT), Universität Innsbruck (AT), Czech Academy of Sciences (CZ), Age UK (GB), Paul Scherrer Institute (CH), Cambridge Crystallographic Data Centre (GB), Christian Doppler Laboratory for Thermoelectricity (AT), Vi Technology (United States) (US), Ruđer Bošković Institute (HR), Rede de Química e Tecnologia (PT), Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ), University College London (GB), University of Warsaw (PL), University of Turin (IT), Université de Rouen Normandie (FR), University of Chemistry and Technology, Prague (CZ)
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Drug Solubulity and Delivery Systems
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