Impact of sodium chloride on the expansion of a liquid-liquid miscibility gap in an API/water system. Case study of Brivaracetam

Int J Pharm. 2016 Dec 30;515(1-2):702-707. doi: 10.1016/j.ijpharm.2016.11.003. Epub 2016 Nov 3.

Abstract

Brivaracetam, or (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide, is an active pharmaceutical ingredient designed for the treatment of epilepsy. During the development of the IV administration mode, a liquid-liquid miscibility gap has been observed with pure water, isotonic and hypertonic solutions (vehicle at 0.9% w/w and 5%w/w NaCl respectively). The study reveals that the NaCl concentration has a direct impact on the extent of the demixing domain; from a sub-micronic demixing in pure water towards a macroscopic miscibility gap in hypertonic aqueous solutions. The thorough exploration of these heterogeneous equilibria led to define experimental parameters for safe IV injections without risk of liquid - liquid miscibility gap at 37°C.

Keywords: Brivaracetam; Brivaracetam (PubChem CID: 9837243); IV administration; Liquid-liquid miscibility gap; Monotectic invariant; Phase diagrams; Tyndall effect.

MeSH terms

  • Administration, Intravesical
  • Pyrrolidinones / administration & dosage
  • Pyrrolidinones / chemistry*
  • Sodium Chloride / chemistry*
  • Solutions / chemistry
  • Water / chemistry*

Substances

  • Pyrrolidinones
  • Solutions
  • Water
  • Sodium Chloride
  • brivaracetam