Paper Citing NAMD - Abstract
Gao, Yi; Olsen, Kenneth W.
Unique Mechanism of Facile Polymorphic Conversion of Acetaminophen in Aqueous Medium
MOLECULAR PHARMACEUTICS, 11:3056-3067, SEP 2014
Rapid polymorphic conversion of acetaminophen (APAP) in solution, from metastable orthorhombic Form II to the stable monoclinic Form I, is well-known. The mechanism is believed to be solution-mediated phase transformation (SMPT), but with little experimental evidence. The present study was undertaken to understand this phenomenon from both thermodynamic and kinetic perspectives. Reliable apparent solubility of Form II was measured, for the first time, in 0.15 M aqueous NaCl solution at 37 degrees C. The solubility ratio of Form II over Form I, 1.27 +/- 0.04, is quite low, which translates to a relatively low thermodynamic driving force for the conversion. Further solution crystallization experiments at supersaturation levels equal to or much greater than Form II solubility did not result in any crystallization in 10 days. Therefore, fast conversion is not possible through SMPT. To explore alternative mechanisms, molecular dynamics (MD) simulations were conducted to investigate the molecular level dissolution behavior and the solid state differences between the two polymorphs. The MD simulations reveal very different behavior. Form II exhibits a much higher rate of H-bond breakage, leading to the accumulation of a large number of disordered APAP molecules on the crystal surface. This thick disordered molecular layer provides a high local acetaminophen concentration which could be responsible for the fast crystallization of Form I. This was further supported by the observations made, using polarized light microscopy and powder X-ray diffractometry, when monitoring Form II crystals coming into contact with NaCI solution. We thus concluded that the hydrated surface layer is the "catalyst" for the facile phase conversion. This new mechanism, termed as SurFPT (surface-facilitated phase transformation), is much more effective in promoting polymorphic transformation than the well-known SMPT.
