Candida antartica lipase b mediated kinetic resolution of racemic acebutolol
| dc.contributor.author | Mariani Rajin | |
| dc.date.accessioned | 2021-04-23T02:00:03Z | |
| dc.date.available | 2021-04-23T02:00:03Z | |
| dc.date.issued | 2015-10-01 | |
| dc.description.abstract | Acebutotol is still available in racemic form. The increasing preference for single or pure enantiomer of chiral drugs is driven mainly by the different effects of the enantiomers, the high market demand and the guidelines issued by regulatory authorities. Therefore, the kinetic resolution of racemic acebutolol is studied in batch and enzymatic membrane reactor. The response surface methodology based on central composite design (CCD) was employed for optimization and analysis of kinetic resolution of racemic acebutolol in a batch reactor. The process variables which were taken into account include; enzyme loading, substrate concentration, acyl donor concentration and temperature. The optimum conditions were found to be 320 mg of enzyme loading, with acebutolol concentration of 50 mM, vinyl acetate concentration of 140 mM and temperature at 40 oC, giving the overall conversion of 46.6%. The value of enantioselectivity E and enantiomeric excess of the substrate ees were found to be 15 and 73%, respectively. Lipase activation and deactivation energy was estimated to be 39.63 kJ/mol and 54.90 kJ/mol, respectively. Denaturation constant, kd was increasing from 0.012-0.031 h-1 with the increasing temperature from 45 0C to 60 0C. The value of enthalpy and entropy for free Candida antartica lipase B were 52.12 kJ/mol.K and -0.18 kJ/mol.K, respectively. Based on the finding from the batch reaction, kinetic resolution of acebutolol has been successfully conducted in enzymatic membrane reactor (EMR). The effects of enzyme loading, substrate and acyl donor concentration, pH of buffer solution,reaction temperature, and organic phase flow rates, and transmembrane pressure (TMP) were investigated. The optimum operating conditions for the lipase-catalyzed kinetic resolution in an EMR system were pH 7, 40 oC and TMP of 6 psi at organic flow rate of 40 ml/min. This condition gave 40% overall conversion, enentioselectivity of 23 and ees of 84%. The reaction kinetic was found to obey the Ping Pong Bi Bi mechanisms for both free and immobilized lipase from Candida antartica B . The kinetic parameters for the free lipase were: KMace =8.53 mM, KMva =5.19 mM, and Vmax =1.18 mM/h. The apparent kinetic parameters for the immobilized lipase were: Kmace app = 2.13 mM, KMvaapp = 1.23 mM and Vmax app =2.33 mM/h. The kinetics of kinetic resolution accounted for both substrates inhibitions. The inhibition constants were given by KIace=10.72 mM, KIva,= 3.71 mM, KIace app = 11.56 mM and KIva app=3.89 mM. The performance of free and immobilized CALB were compared. The immobilized lipase in EMR gave higher reaction capacity, better thermal stability, higher affinity to the substrates and exhibited higher resistance towards the inhibition effect. The advantages of immobilized enzyme makes it possible for economical industrial production of chiral drugs, particularly beta blockers in the near future. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/13094 | |
| dc.language.iso | en | en_US |
| dc.subject.lcsh | Candida | |
| dc.title | Candida antartica lipase b mediated kinetic resolution of racemic acebutolol | en_US |
| dc.type | Thesis | en_US |
Files
License bundle
1 - 1 of 1
Loading...
- Name:
- license.txt
- Size:
- 1.71 KB
- Format:
- Item-specific license agreed upon to submission
- Description: