Optimization of enantioselective resolution of racemic ibuprofen by native lipase from Aspergillus niger

Abstract

Resolution of (R,S)-ibuprofen (2-(4-isobutylphenyl)propionic acid) enantiomers by esterification reaction with 1-propanol in different organic solvents was studied using native Aspergillus niger lipase. The main variables controlling the process (enzyme concentration and 1-propanol:ibuprofen molar ratio) have been optimized using response surface methodology based on a five-level, two-variable central composite rotatable design, in which the selected objective function was enantioselectivity. This enzyme preparation showed preferentially catalyzes the esterification of R(-)-ibuprofen, and under optimum conditions (7% w/v of enzyme and molar ratio of 2.41:1) the enantiomeric excess of active S(+)-ibuprofen and total conversion values were 79.1 and 48.0%, respectively, and the E-value was 32, after 168 h of reaction in isooctane.

Characterization and catalytic activity of free and immobilized lipase from Aspergillus niger: a comparative study

“…21 Different strategies have been reported in the previous studies of our research group to improve the enantioselectivity of this lipase, such as the use of ionic liquids 7 and optimization of reaction medium. 2 After optimization of several reaction conditions (type and ratios of isooctane/ionic liquid, amount of enzyme and reaction time), the E-value of Aspergillus niger lipase (15%, m/v) could be duplicated (E = 9.2) in a solvent system composed of [BMIM] [PF 6 ] and isooctane (1:1) after 96 h of reaction. 7 These tests were performed using the crude free enzyme lyophilized extract in higher concentrations than those used in the current study.…”

“…1,2 The enantiomeric differentiation of lipases is used to separate racemic mixtures of chiral esters, hydrolyzing preferentially one enantiomer or through esterification reactions of chiral acids and/or chiral alcohols. The versatility of these biocatalysts, when used in organic solvents, allows attainment of a great variety of other pharmaceutical intermediates.…”

Cyclic resolution of racemic ibuprofen via coupled efficient lipase and acid‐base catalysis

“…Recently, Candida rugosa lipase, 15,16 Rhizomucor miehei lipase, 17 and Aspergillus niger lipase 8 have been used for the chiral resolution of (R,S)-ibuprofen through mainly direct enantioselective esterification in organic media; Lipase from C. rugosa (Type VII), 18,19 Pseudomonas cepacia lipase, 20 and Pseudomonas fluorescens lipase 21 have been used to catalyze enantioselective hydrolysis of its chemically synthesized racemic ester.…”

“…7 (S)-ibuprofen has been available since 1994, but until recently, all except naproxen and flunoxaprofen have been marketed and consumed as racemic mixtures. 8 Today, due to doselimiting, toxicity, and pharmacokinetics, there is an increasing interest in obtaining the pure enantiomeric form of biologically active drugs to prevent any side effects from using racemic mixture. A number of approaches to prepare it in optically pure form, including resolution of diastereomeric salts, resolution of racemates, and asymmetric syntheses using chiral auxiliaries and chiral catalysts have been proposed.…”

Purification and Application of a Lipase from Penicillium expansum PED-03

“…The enantioselectivity of P. expansum PED-03 lipase for ibuprofen was excellent. The selectivity with an enantiomeric ratio E of 536 was much higher than that of those lipases from C. rugosa [5], R. miehei [8], Aspergillus niger [20] (Table 3).…”