Commercially viable resolution of ibuprofen

Area of Science:

• Biocatalysis
• Enzyme Engineering
• Pharmaceutical Chemistry

Background:

• Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) belonging to the profen class.
• (S)-ibuprofen exhibits significantly higher potency than (R)-ibuprofen.
• Accumulation of (R)-ibuprofen is linked to adverse gastrointestinal effects.

Purpose of the Study:

• To develop an enantioselective biocatalytic method for producing pure (S)-ibuprofen.
• To utilize Candida rugosa lipase for efficient esterification and hydrolysis of ibuprofen enantiomers.
• To achieve high enantiomeric excess of (S)-ibuprofen while minimizing the presence of (R)-ibuprofen.

Main Methods:

• Enantioselective esterification of racemic ibuprofen with decan-1-ol and butan-1-ol using Candida rugosa lipase in cyclohexane.
• Separation of (R)-ibuprofen and (S)-alkyl ibuprofen esters via bulb-to-bulb distillation.
• Enantioselective hydrolysis of (S)-alkyl ibuprofen esters using the same biocatalyst in an aqueous buffer.

Main Results:

• Enantioselective esterification achieved enantiomeric ratios (E) of 130 for decyl and 46 for butyl esters, with up to 46% conversion.
• Successful separation of decyl ester from (R)-ibuprofen and unreacted alcohol.
• Enantioselective hydrolysis was twice as fast for the butyl ester compared to the decyl ester.

Conclusions:

• The combined enantioselective esterification and hydrolysis process efficiently isolated (S)-ibuprofen.
• The method yielded (S)-ibuprofen with a high enantiomeric excess (>99%).
• This biocatalytic approach offers an environmentally friendly route to pure (S)-ibuprofen, reducing potential side effects from the (R)-enantiomer.