Nose Temperature and Anticorrelation between Recrystallization Kinetics and Molecular Relaxation Dynamics in Amorphous Morniflumate at High Pressure

Mol Pharm. 2019 Aug 5;16(8):3514-3523. doi: 10.1021/acs.molpharmaceut.9b00351. Epub 2019 Jul 18.

Abstract

We probe the dielectric response of the supercooled liquid phase of Morniflumate, a drug with anti-inflammatory and antipyretic properties, studying in particular the pressure and temperature dependence of the relaxation dynamics, glass transition temperature Tg, and recrystallization kinetics. Tg increases by roughly 20 K every 100 MPa at low applied pressure, where the ratio Tg/Tm has a constant value of ∼0.8 (Tm = melting point). Liquid Morniflumate displays two dielectric relaxations: the structural α relaxation associated with the collective reorientational motions, which become arrested at Tg, and a secondary relaxation likely corresponding to an intramolecular dynamics. The relaxation times of both processes scale approximately with the inverse reduced temperature Tg/T. Near room temperature and under an applied pressure of 50 MPa, supercooled Morniflumate recrystallizes in a characteristic time of few hours, with an Avrami exponent of 1.15. Under these conditions, the recrystallization rate is a nonmonotonic function of temperature, displaying a maximum at around 298 K, which can be taken to be the optimum crystal growth temperature Tnose. The β relaxation becomes kinetically frozen at ambient temperature under an applied hydrostatic pressure higher than 320 MPa, suggesting that the Morniflumate glass should be kinetically stable under these conditions.

Keywords: dielectric spectroscopy; glassy drug stability; optimum crystal growth temperature; recrystallization kinetics; secondary relaxation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemistry*
  • Crystallization
  • Dielectric Spectroscopy
  • Hydrostatic Pressure
  • Kinetics
  • Molecular Dynamics Simulation
  • Niflumic Acid / analogs & derivatives*
  • Niflumic Acid / chemistry
  • Phase Transition
  • Transition Temperature*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Niflumic Acid
  • morniflumate