title: Solid-state transformations of ribavirin as a result of high-shear mechanical processing.
abstract: Ribavirin (C8H12N4O5; anti-viral agent) was crystallized as two unique, phase-pure polymorphs (R-I and R-II). Calorimetrically determined isobaric heat capacities and heat of transition data were utilized to determine the solid-state transition temperature (Ttr), confirming enantiotropism, while R-I was determined to be kinetically stable at ambient temperature. Unprocessed samples of the low Tmpolymorph, R-II, did not convert into R-I when held isothermally well above Ttrfor 7days. In contrast milled R-II completely transformed to R-I after 15min at the same storage conditions, indicating that defects sustained during processing reduced the energy barrier for transformation, allowing it to occur. R-II was subjected to both cryogenic milling and impact milling at ambient temperature for various durations. Cryomilling resulted in an in situ progressive reduction of crystallinity, with complete conversion to amorphous ribavirin after 2h. Limited molecular mobility attributable to the low milling temperature (Texp=-196°C) likely inhibited recrystallization, allowing the amorphous solid to persist. In contrast, continuous impact milling at ambient temperature resulted in complete in situ conversion from R-II to R-I after 3h. The data suggested rapid conversion to R-I from highly disordered regions during extended milling, facilitated by localized heat buildup that likely exceeded Tgand/or Ttr.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. Electronic address: vasad@duq.edu.
authors.forename: Dipy M
authors.initials: DM
authors.lastname: Vasa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. Electronic address: wildfongp@duq.edu.
authors.forename: Peter L D
authors.initials: PLD
authors.lastname: Wildfong
mesh_terms: D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D006358:Hot Temperature; D012254:Ribavirin / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D012254:Ribavirin
keywords: Amorphous; Mechanical activation; Polymorphism; Ribavirin; Thermal stress; Transition temperature