Demonstration of Molecular Purification in Polar Aprotic Solvents by Organic Solvent Nanofiltration

Abstract

Common separation challenges in the synthesis of active pharmaceutical ingredients (APIs) and production of high-value natural compounds (HVNCs) often involve molecules of molecular weight less than 1000 g · mol -1 . Examples are the removal of lower/ higher molecular weight (MW) byproduct from an intermediate in API production, or the removal of free fatty acids (MW 200-300 g · mol -1 ) from glycerides (MW 600-800 g · mol -1 ) in natural oils. Here we show how organic solvent nanofiltration (OSN) can be applied to typical separation challenges. Two dyes, SolWent Yellow 7 (MW ) 198.2 g · mol -1 ) (SY7) and Brilliant Blue R (MW ) 826.0 g · mol -1 ) (BB), are used in Case Study A as model product and impurity compounds, respectively. Case Study B is an actual separation challenge at Janssen Pharmacuetica NV involving an intermediate of a new drug candidate (API-INT, MW) 675 g · mol -1 ) and its oligomeric impurities (MW g 1000 g · mol -1 ). Solutions to these separation challenges are demonstrated using organic solvent nanofiltration (OSN) spiral-wound membrane modules, applying diafiltration at kilo scale with typical organic solvents, N,N-dimethylformamide (DMF) and tetrahydrofuran (THF). For Case Study A, a final product with 99.7% purity of SY7 was generated from an initial starting solution of 91% purity, while recovering 90% of SY7. For Case Study B, 99% of the higher MW oligomeric impurities (i.e., tetramer and higher) have been removed from API-INT, whilst reducing the content of oligomeric impurities in the synthesis solution from 6.8 wt % to 2.4 wt %, which is below the allowed limit of 3 wt % oligomeric impurities, and recovering more than 99% of API-INT. By applying OSN, a solution is demonstrated to the tedious separation problem posed by Case Study B, which standard separation techniques (including chromatography, crystallization and charcoal treatment) cannot achieve. However, OSN diafiltration processes can require a large volume of solvent to achieve the target purity and yield of the desired compound. Coupling the purification process with a downstream OSN-solvent recovery system (dual membrane diafiltration (DMD)) provides a solvent-efficient process, which does not generate large volumes of waste and/or does not provide a dilute product solution that would require further processing.Operation of the spiral-wound modules in DMF and THF up to 10 days and 120 days, respectively showed that the membrane modules have stable flux and consistent separation performances over time. A simple mathematical tool is used to assist in membrane selection as well as in designing an efficient process configuration.

Solvent recycle with imperfect membranes: A semi-continuous workaround for diafiltration

“…Several authors have worked towards implementing some form of solvent recovery in OSN applications, with common techniques including non-selective adsorption [4,5], hybrid distillation [6] or hybrid chromatography [7] processes, as well as recovery solely through low-molecular cut-off membranes [4,[8][9][10][11]. In most of these implementations, membrane-based solvent recovery promises advantages over traditional methods of solvent recovery with regards to energy consumption and sustainability.…”

“…[8,9] In one example, solvent recovery was achieved due to the fact that the higher molecular weight species was the impurities, and rejections for the product and oligomer impurities in the solvent recovery stage were ≥ 99.5 and ≥ 99.9 %, respectively. [8] In the other study, the impurity (triphenylmethanol, MW = 266.33 g.mol -1 ) was smaller but, presumably due to its bulky nature, still highly rejected by the solvent recovery membranes (R SR = 99.8 %), allowing removal of 97 % of the impurity in a single continuous diafiltration run. [9] It was established that in a closed loop system where rejection of the solvent recovery stage is not absolute, complete removal of the impurity cannot be achieved due to trace amounts of impurity leaching back into the separation stage.…”

Nanofiltration process for the nutritional enrichment and refining of rice bran oil

“…Recently, membrane technology, particularly organic solvent nanofiltration (OSN), has attracted attention as an alternative molecular separation technology (Nasso and Livingston, 2008 Sereewatthanawut et al, 2010). One of the key problems of processing natural compounds is that they are often susceptible to thermal damage, and thus the mild (near-ambient) operating conditions of membrane processes can minimise nutritional losses due to thermal degradation.…”

Comparison of two nanofiltration membrane reactors for a model reaction of olefin metathesis achieved in toluene

“…Observed retentions of pre-catalysts were calculated according to Equation 6 with a precision of 3 %.…”