Sulfamerazine: Understanding the Influence of Slip Planes in the Polymorphic Phase Transformation through X-Ray Crystallographic Studies and ab Initio Lattice Dynamics

Abstract

Understanding the polymorphism exhibited by organic active-pharmaceutical ingredients (APIs), in particular 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 article, we report a detailed study of the structure-property relationships among the polymorphs of the model API, Sulfamerazine. Detailed experimental characterization using synchrotron radiation is complemented by computational modeling of the lattice dynamics and mechanical properties, in order to study the origin of differences in millability and to investigate the thermodynamics of the phase equilibria. Good agreement is observed between the simulated phonon spectra and mid-infrared and Raman spectra. The presence of slip planes, which are found to give rise to 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 that is difficult to isolate. The combined experimental and theoretical approach employed here should be generally applicable to the study of other systems that exhibit polymorphism.

Intrinsic Flexibility of the EMT Zeolite Framework Under Pressure

“…However, at higher temperatures differences in the vibrational free energy outweigh the difference in lattice energy and render EMT the more stable polymorph, with a free-energy difference of +2.39 kJ mol −1 (2.49 × 10 −2 kJ mol −1 per F.U.) at 300 K. A decomposition of ∆A into ∆U and −T∆S terms shows clearly that this stabilisation arises from the higher vibrational entropy of the EMT framework compared to FAU, a conclusion in line with similar studies on other materials [42,43].…”

“…As noted in previous studies [42,43], subtle differences in lattice dynamics and vibrational contributions to the free energy can also adjust the stability ordering of competing polymorphs at finite temperature. To investigate this, we performed lattice dynamics calculations with PBEsol + D3 on the FAU and EMT frameworks, from which we evaluated the temperature-dependent constant-volume (Helmholtz) free energy A = U − TS according to: [44]…”

Lattice dynamics of Pnma Sn(S1–xSex) solid solutions: energetics, phonon spectra and thermal transport

“…Again taking the x Se =0.5 model as an example, the largest difference in E n between two structures is 3.8 meV atom −1 (0.36 kJ mol −1 atom −1 ), whereas the difference in the zero point energies is 0.06 kJ mol −1 atom −1 and the difference in A n vib at 900 K is 2.06 kJ mol −1 atom −1 . Given the number of examples in the literature showing that differences in vibrational free energy-in particular the vibrational entropy-are a key driver of temperature-induced phase transitions [42,[44][45][46], and are important in the determining the stability of alloy systems [43,47,48], this finding is not surprising, but is nonetheless noteworthy.…”

Application of Vibrational Spectroscopy to Study Solid-state Transformations of Pharmaceuticals

“…The relationship between the presence of slip planes, very low-energy lattice vibrations, millability and mechanical and thermodynamic instability is discussed in the literature [192]. Quantitative monitoring of the cryomillinginduced amorphization of sulfamerazine form I and form II showed that form I was fully amorphous after 30 min, while milling for 2 h was required to convert form II to the amorphous phase [121].…”

“…The slip planes of form I also lead to higher plasticity, compressability and tabletability compared to form II [194]. A recent combined theoretical and experimental study using ab initio lattice dynamics calculations, Raman spectroscopy and temperaturedependent X-ray analysis gave further insight into the origin of the different mechanical properties of the polymorphs of sulfamerazine [192]. Raman spectroscopy was used to identify the low-frequency collective motions that are particularly low in energy and thermally accessible at low to moderate temperatures in order to understand how the structure may preferentially deform under mechanical shear during milling.…”