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

## TL;DR

This study investigates the different crystal forms of sulfamerazine, a drug, and highlights the challenges in modeling their thermodynamic behavior.

## Contribution

The discovery of a new polymorph, form V, and its implications for phase diagram modeling and computational energy models.

## Key findings

- Form II of sulfamerazine can be obtained by slurrying in acetonitrile/water at room temperature.
- A new polymorph, form V, was identified as a polytype of form I with a different packing arrangement.
- The enthalpy of transition from form II to form I at 150 °C is 3.15 ± 0.12 kJ mol–1.

## 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 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.