471664 The Use of Ionic Liquids for API Purifications and Its Effect on Nucleation Kinetics
Samir A. Kulkarnia,b*, Cameron C. Webera,c, and Allan S. Myersona
a Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
b SSCI, A Division of Albany Molecular Research, Inc. (AMRI), 3065 Kent Avenue West Lafayette, IN 47906-1076
c Department of Chemistry, Imperial College London, London SW7 2AZ, UK
Keywords: Crystallization, Nucleation, Ionic Liquids
The source of this interest arises from the favorable properties some Ionic Liquids can exhibit, such as low flammability, low vapor pressures, tunable physicochemical properties through appropriate ion selection, large liquidus ranges and good thermal stability. The tunability of Ionic Liquids has been one of their most widely touted and exploited benefits as solvents, as the ability to manipulate solution interactions can lead to the design of Ionic Liquids that are good solvents for chosen target compounds. This has been explored with regards to the solubility of pharmaceutical substances, and their crystallization. These approaches typically involve the use of antisolvent crystallization or a combination of liquid-liquid extraction and antisolvent crystallization to recover the target . Surprisingly, studies into the use of Ionic Liquids as solvents for the purification by crystallization of organic solids, particularly pharmaceuticals, remains relatively limited despite the industrial significance of this methodology. In order to address these concerns we have considered the use of cooling crystallization in an Ionic Liquid as a purification methodology to reduce the complexity of the resultant solution. The Ionic Liquid possesses a relatively high viscosity over a wide range of temperature and the high initial viscosity can act as kinetic barrier to both nucleation and subsequent crystallization .
To ascertain the generality of our approach and to probe the limits of miscibility and thermal stability, we have examined a wide range of different active pharmaceutical compounds (APIs) as model systems for the cooling crystallization approach . To demonstrate proof of principle and examine the efficacy of this purification approach, the cooling crystallization of acetaminophen with various impurities has been conducted and compared with results obtained for antisolvent processes and with cooling crystallizations conducted in water. The results in all cases indicated that impurity inclusion was comparable or improved compared to antisolvent crystallizations from either water, organic solvent systems or Ionic Liquids with substantially improved yields. Such a straightforward crystallization approach taking advantage of the low vapor pressure and wide ranging miscibility of ionic liquids with various solvents suggests a route towards a general purification procedure for many small molecule APIs in Ionic Liquids. The ionic liquid displayed a diverse effect on nucleation kinetics, as ionic liquid was more effective than ethanol-water system to reduce nucleation rate and to enhance growth time. Specific ionic liquids thus provide an additional tool in nucleation control in solution crystallization.
1. CC Weber, AJ Kunov-Kruse, RD Rogers, AS Myerson, Manipulation of ionic liquid anion–solute–antisolvent interactions for the purification of acetaminophen, Chem. Commun., 2015,51, 4294-4297.
2. Kulkarni SA, Kadam SS, Meekes H, Stankiewicz AI, ter Horst JH (2013) Crystal Nucleation Kinetics from Induction Times and Metastable Zone Widths. Crystal Growth & Design 13 (6):2435-2440.
3. Cameron C Weber, Samir A Kulkarni, Andreas J Kunov-Kruse, Robin D Rogers, Allan S Myerson The Use of Cooling Crystallization in an Ionic Liquid System for the Purification of Pharmaceuticals. Cryst. Growth Des., 2015, 15 (10), pp 4946–4951.