2-Methyl tetrahydrofuran: a green organic modifier for eco-friendly, cost-effective, and rapid purification in drug discovery†

Abstract

The current need to make processes greener encourages us to reduce solvent consumption along with replacing hazardous solvents with ecofriendly solvents. Analytical purification is one of the most solvent-consuming processes in drug discovery, and our present study is a step forward, making it ecofriendly, fast, and cost-effective. Our study evaluated 2-methyl tetrahydrofuran (MTHF) as a sustainable alternative to THF in reverse-phase HPLC, focusing on its impact on peak shapes, resolution, retention time, and sample loading. We screened six commercially available hydrochloride salts of +epinephrine (1), tetramisole (2), acebutolol (3), labetalol (4), +verapamil (5), and amitriptyline (6) with varying polarity indexes using multiple mobile phase combinations, including ACN, ACN–MeOH, 5% MTHF in ACN, and 5% MTHF in ACN–MeOH, alongside various buffers. The choice of ACN and MeOH is based on their remarkable properties, such as complete miscibility with water, relatively low viscosity, low UV cut-off, and low chemical reactivity. This multi-step screening in combination with various buffers (different pH) and solvents was required for identifying the optimal role of MTHF for achieving the best chromatographic performance with the selected analytes. The study showed that using TFA buffer with 10% MTHF in ACN–MeOH has significantly enhanced the peak shape and resolution, which facilitates approximately five-fold higher sample loading as compared to ACN–MeOH alone. This approach resulted in a shorter run time, reducing organic solvent consumption by ∼87% and the overall turnaround time by approximately ∼89%. Thus, the study validates MTHF as a green solvent for high-throughput, cost-effective purification of complex mixtures of small molecules.