Impact of sodium chloride on the expansion of a liquid-liquid miscibility gap in an API/water system. Case study of Brivaracetam.
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.
Normandie Université, Laboratoire SMS-EA3233, Univ Rouen, F-76821 Mont Saint Aignan, France. Electronic address: nicolas.couvrat@univ-rouen.fr.
Nicolas
N
Couvrat
Nestec SA research center Nestlé, Route du Jorat 57, 1000, Lausanne 26, Switzerland. Electronic address: julien.mahieux@rdls.nestle.com.
Julien
J
Mahieux
Minakem Recherche, 145, Chemin des Lilas, F-59310 Beuvry-la-Forêt, France. Electronic address: baptiste.fours@minakem.com.
Baptiste
B
Fours
Normandie Université, Laboratoire SMS-EA3233, Univ Rouen, F-76821 Mont Saint Aignan, France. Electronic address: yohann.cartigny@univ-rouen.fr.
Yohann
Y
Cartigny
UCB Pharma S.A., Chemin du Foriest, B - 1420 Braine-l'Alleud, Belgium. Electronic address: eric.schenkel@ucb.com.
Eric
E
Schenkel
UCB Pharma S.A., Chemin du Foriest, B - 1420 Braine-l'Alleud, Belgium. Electronic address: luc.aerts@ucb.com.
Luc
L
Aerts
UCB Pharma S.A., Chemin du Foriest, B - 1420 Braine-l'Alleud, Belgium. Electronic address: luc.quere@ucb.com.
Luc
L
Quéré
Normandie Université, Laboratoire SMS-EA3233, Univ Rouen, F-76821 Mont Saint Aignan, France. Electronic address: gerard.coquerel@univ-rouen.fr.
Gérard
G
Coquerel
D000283:Administration, Intravesical; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000737:chemistry*; D012965:Sodium Chloride / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry; D014867:Water / Q000737:chemistry*
D011760:Pyrrolidinones; D012996:Solutions; D014867:Water; D012965:Sodium Chloride; C482793:brivaracetam
Brivaracetam; Brivaracetam (PubChem CID: 9837243); IV administration; Liquid-liquid miscibility gap; Monotectic invariant; Phase diagrams; Tyndall effect