키랄 고정상을 이용한 라세미 이브프로펜의 광학분할

송태호; 서성섭; 최민호; 김영대; 이중기; 박달근; Taeho Song; Sung-Sup Suh; Min-Ho Choi; Young Dae Kim; Joong Kee Lee; Dalkeun Park

HWAHAK KONGHAK, Vol.38, No.3, 373-379, June, 2000

Export Citation

키랄 고정상을 이용한 라세미 이브프로펜의 광학분할

Optical Resolution of Racemic Ibuprofen by using Chiral Stationary Phase

송태호, 서성섭 , 최민호, 김영대 ¹, 이중기 ^{2, †}, 박달근 ²

홍익대학교 화학공학과
¹전남대학교 응용화학부
²한국과학기술연구원 청정기술연구센터

Taeho Song, Sung-Sup Suh , Min-Ho Choi, Young Dae Kim¹, Joong Kee Lee^{2, †}, and Dalkeun Park²

Department of Chemcal Engineering, Hongik University, Korea
¹Faculty of Applied Chemistry, Chonnam National University, Korea
²Clean Technology Research Center, Korea Institute of Science and Technology, Korea

E-mail:

초록

비스테로이드 계통의 진통 및 소염제로서 널리 사용되어지고 있는 광학 이성질체 혼합물인 라세미 이브프로펜(racemic Ibuprofen)을 분리하기 위하여 여러 가지 키랄 HPLC 칼럼 고정상들을 사용하였다. 고정상으로는 β-CD(β-cyclodextrin) BR^R, ODS-H80^R, Kromasil^R,β-CD가 사용되었다. 라세미 이브프로펜 중에서 오직 S-(+)-enantiomer만이 약리적 활성이 존재하므로 이브프로펜 대장체(enantiomer)들을 HPLC 이용하여 광학분할을 수행하면서 적합한 분리조건을 조사하였다. 이브프로펜의 분리도와 분리인자는 사용되어진 키랄 고정상들과 이동상의 조성비에 크게 영향을 받는다는 것을 알 수 있었다. 4개의 키랄 고정상 중에서 β-CD BR^R과 Kromasil^R 키랄 고정상에서 이브프로펜의 광학분할이 가능하였다. 각각의 고정상 물질에 따라 적합한 이동상 조성비는 다르게 얻어졌으며, 분리인자 (separation factor)의 증가는 항상 분리도(resolution)의 중가와 일치하지 않았다. 칼럼 효율에 영향을 주는 공정 변수를 조사하였는데 주입부피가 증가함에 따라서 분리도는 감소하였으나 이동상 유속이 증가함에 따라 주입부피의 증가가 분리도에 미치는 영향은 다소 적은 것을 알 수 있었다. β-CD BR^R과 Kromasil^R 칼럼을 사용하여 이동상 유속, 주입부피 그리고 주입농도가 이브프로펜의 분리에 미치는 영향을 조사하여 보았다. 5,000ppm 이상의 이브프로펜 농도 증가에 대해 피크 형태는 약간 비대칭 경향을 갖고 있지만 100,000ppm 이하의 농도에서 이브프로펜의 분리도는 1.5이상을 유지하였고 피크 형태에 있어서도 끌림 현상 (tailing)이 거의 없어 농도의 변화에 따라 물질전달의 영향이 별로 달라지지 않음을 유추할 수 있었다.

Various chiral HPLC stationary phases were employed for the separation of racemic Ibupofen which is widely used as non-steroidal analgetic and anti-inflammatory agent. Since the pharmacological activity resides in the (S)-(+)-enantiomer only, the optical separation of Ibuprofen enantiomers was carried out and compatible separation conditions were investigated. β-CD BR^R, ODS-H80^R, Kromasil^R, and β-CD were used as the chiral stationary phases(CSPs). The resolution and selectivity of Ibuprofen were found to be strongly by the employed CSPs and composition of eluents. A comparison of the four CSPs showed that β-CD BR^R and Kromasil^R CSP could separate Ibuprofen enantiomers. The optimum composition of each eluent was obtained differently for each stationary material phase. The increase of selectivity did not always result in the increase of resolution. Process variables effecting column performance were investigated. Resolution decreased with the increase of injection volume, but the increase of injection volume had less effect on the resolution as flow rate increased. The influence of the flow rate, injection volume, and concentration on Ibuprofen enantiomers separation was studied using β-CD BR^R and Kromasil^R columns. The chromatogram had slightly nonsymmetric form at the concentration over 5,000ppm; nevertheless, the resolution was more than 1.5 at the concentration below 100,000ppm. The form of peak which hardly had tailing showed that mass transfer effect nearly changed with the concentration.

Keywords:Ibuprofen;enantiomer;Separation;HPLC;Chiral Stationary Phase

[References]

Wellie LH, Terrence ER, Anal. Chem., 57, 237 (1985)
Cho OS, Kim OD, "Research on the Development of High Efficiency Separation System," KIST annual report UCE1526-6343-6 (1999)
Ravi B, Jurgen M, Biomedical Chromatography, 12, 309 (1998)
Yoshio O, Ryo A, Kazuhiro H, Koichi H, J. Liquid Chromatography, 11(9-10), 2147 (1988)
Tan SC, Jackson SHD, Swift CG, Hutt AJ, J. Chromatogr. B, 53, 701 (1997)
Wright MR, Sattari S, Brocks DR, Jamali F, J. Chromatogr. Bimed. Appl., 259, 121 (1992)
Armstrong DW, Anal. Chem., 59, 84A (1987)
Pirkle WH, Pochapsky TC, "Advances in Chromatography," J.C. Giddings, ed., Marcel Dekker, New York, 27, Chap 3 (1987)
Pirkle WH, Finn J, in J. Morrison(Ed.), "Asymmetric Synthesis," Academic Press, New York, 1, Chap 6 (1983)
Lochmuller CH, Souter RW, J. Chromatogr., 283, 113 (1973)
Pirkle WH, Finn JM, in J.D. Morrison(Ed.), "Asymmetric Synthesis," Academic Press, New York, 1, 87 (1983)
Allenmark SJ, Biochem. Biophys. Method, 1, 9 (1984)
Minoru T, Yoshihiro K, Mitsugu N, Yoshikazu M, Toshiyuki S, J. Chromatogr., 299, 341 (1984)
Lippmann T, Hartenstein H, Sicker D, Chromatographia, 35(5-6), 302 (1993)
Song L, William Purdy C, J. Chromatogr., 109, 625 (1992)
Pirkle WH, Pochapsky TC, J. Am. Chem. Soc., 108, 5627 (1986)
Pirkle WH, Pochapsky TC, J. Am. Chem. Soc., 109, 5975 (1987)
Kim TJ, Lee JS, "A Study on the Separation, Analysis or Interpretation of Valuable Material," KIST The third year last report (1992)
Hyun MH, "Preparation and Evaluation of a Chiral Stationary Phase Bearing Both-Acidic and -Basic Sites," Korea Science and Engineering Foundation, Project Number (863-0302-005-1) (1987)
Lederer K, Amtmann L, Vijaykumar S, Billiani J, J. Liquid Chromatography, 13, 1849 (1990)
Gallagher W, Woodward C, Biopolymers, 28, 2001 (1989)
Gibbs S, Chu A, Lightfoot E, Root T, J. Phys. Chem., 93, 467 (1991)
Al-Duri B, McKay G, J. Chem. Technol. Biotechnol., 55, 245 (1992)
Seidel-Morgenstern A, Jacobson SC, Guiochon G, J. Chromatogr., 19, 637 (1993)

[Referenced By]

[Related Articles]

[1] Wellie LH, Terrence ER, Anal. Chem., 57, 237 (1985)

[2] Cho OS, Kim OD, "Research on the Development of High Efficiency Separation System," KIST annual report UCE1526-6343-6 (1999)

[3] Ravi B, Jurgen M, Biomedical Chromatography, 12, 309 (1998)

[4] Yoshio O, Ryo A, Kazuhiro H, Koichi H, J. Liquid Chromatography, 11(9-10), 2147 (1988)

[5] Tan SC, Jackson SHD, Swift CG, Hutt AJ, J. Chromatogr. B, 53, 701 (1997)

[6] Wright MR, Sattari S, Brocks DR, Jamali F, J. Chromatogr. Bimed. Appl., 259, 121 (1992)

[7] Armstrong DW, Anal. Chem., 59, 84A (1987)

[8] Pirkle WH, Pochapsky TC, "Advances in Chromatography," J.C. Giddings, ed., Marcel Dekker, New York, 27, Chap 3 (1987)

[9] Pirkle WH, Finn J, in J. Morrison(Ed.), "Asymmetric Synthesis," Academic Press, New York, 1, Chap 6 (1983)

[10] Lochmuller CH, Souter RW, J. Chromatogr., 283, 113 (1973)

[11] Pirkle WH, Finn JM, in J.D. Morrison(Ed.), "Asymmetric Synthesis," Academic Press, New York, 1, 87 (1983)

[12] Allenmark SJ, Biochem. Biophys. Method, 1, 9 (1984)

[13] Minoru T, Yoshihiro K, Mitsugu N, Yoshikazu M, Toshiyuki S, J. Chromatogr., 299, 341 (1984)

[14] Lippmann T, Hartenstein H, Sicker D, Chromatographia, 35(5-6), 302 (1993)

[15] Song L, William Purdy C, J. Chromatogr., 109, 625 (1992)

[16] Pirkle WH, Pochapsky TC, J. Am. Chem. Soc., 108, 5627 (1986)

[17] Pirkle WH, Pochapsky TC, J. Am. Chem. Soc., 109, 5975 (1987)

[18] Kim TJ, Lee JS, "A Study on the Separation, Analysis or Interpretation of Valuable Material," KIST The third year last report (1992)

[19] Hyun MH, "Preparation and Evaluation of a Chiral Stationary Phase Bearing Both-Acidic and -Basic Sites," Korea Science and Engineering Foundation, Project Number (863-0302-005-1) (1987)

[20] Lederer K, Amtmann L, Vijaykumar S, Billiani J, J. Liquid Chromatography, 13, 1849 (1990)

[21] Gallagher W, Woodward C, Biopolymers, 28, 2001 (1989)

[22] Gibbs S, Chu A, Lightfoot E, Root T, J. Phys. Chem., 93, 467 (1991)

[23] Al-Duri B, McKay G, J. Chem. Technol. Biotechnol., 55, 245 (1992)

[24] Seidel-Morgenstern A, Jacobson SC, Guiochon G, J. Chromatogr., 19, 637 (1993)