Low-frequency Raman signatures of transient polyamorphic situation in linezolid: A competition between conformational polymorphs

Abstract

This paper reports two bimodal first-order transformations in the disordered form III of linezolid. The most notable result was the identification of a transient apparently amorphous state, different from the glass, during slow heating from the glass. This transient state was interpreted as resulting from the competition between two organizations, i.e., a locally preferred structure reminiscent of the ordered form and the long-range order of the disordered form, energetically closer to the undercooled liquid than the ordered form. The first-order transformation of the undercooled liquid in this short lifetime amorphous state reflects a polyamorphism in a pharmaceutical active ingredient, which is a very unusual feature in the domain of solid-state transformations in molecular materials. Meanwhile, the bimodal polymorphic transformation of the stable crystalline form II into form III via a transient liquid state during rapid heating can also be considered as an uncommon feature for a polymorphic transition. It was found that both atypical transformations assisted by thermally activated conformational motions into the disordered crystalline form III could be kinetically hindered by the high energy barrier between conformational polymorphs. As a consequence, the polyamorphic transformation can only be detected using the rapid acquisition capability of a low-frequency Raman spectrometer, probing the molecular organization from short- to long-range order.