Complexation of Both Enantiomers of 2-Phenylpropionic Acid with Cyclodextrin: Determination of Binding Constant, Stoichiometry, Bioavailability and Co-Conformation

Ali Aboel Dahab, Norman W. Smith

Pharmaceutical Sciences Research Division, King’s College, London, UK.

DOI: 10.4236/jeas.2012.23008                

Abstract

Although enantiomers of 2-phenylpropionic acids (2-PPAs), or profens are important group of nonsteroidal anti-inflammatory drugs (NSAIDs) and have been in clinical use for many years, there is no literature covering its binding interaction in particular with cyclodextrins. NSAIDs are marketed as racemates, chiral discrimination and knowledge of enantiomeric bioavailability is essential. Circular dichroism (CD) spectroscopy is the technique of choice for elucidating chirality and monitoring and characterizing molecular recognition phenomena in solution. Methods em-ploying the fundamentals of the simultaneous measurements of absorbance and CD and a novel efficient titration method have been developed to study the binding of β-Cyclodextrin (β-CyD) and the two enantiomers of 2-PPA as a function of pH. The effect on physicochemical properties and bioavailability was investigated. The binding constant, stoichiometry and pKa for both the free and the bound drugs were determined using a Levenburg-Marquadt non-linear equation. The exact nature of the enantiomer discriminating interactions by cyclodextrins (CyDs) is not well understood. In this work, the interactions and co-conformations of both enantiomers of 2-PPA with β-CyD were explained and es-timated using spectroscopic variations upon complexation. The results indicated a change in the physicochemical prop-erties of 2-PPAs upon complexation and highlighted the enantioselective binding of β-CyD as a function of pH. The charge on the guest molecule and its stereochemistry are of great importance in regulating the stability of the guest/β-CyD complexes; hence the bioavailability of drugs. This work elucidates 2-PPAs/β-CyD binding interactions and highlights the effect of β-CyD on drugs with an effective novel method for binding titration and the potential of the simultaneous measurements of absorbance and CD in future chiral drug interactions studies.

Keywords

β-Cyclodextrin; Binding Constant; Bioavailability; 2-Phenylpropionic Acid; UV and Circular Dichroism

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	C. Varas-Lorenzo, A. Maguire, J. Castellsague and S. PerezGutthann, “Quantitative Assessment of the Gastrointestinal and Cardiovascular Risk-Benefit of Celecoxib Compared to Individual NSAIDs at the Population Level,” Pharmacoepidemiology and Drug Safety, Vol. 16, No. 4, 2007, pp. 366-376. doi:10.1002/pds.1299
[2]	M. M. Krause, M. D. Brand, S. Krauss, C. Meisel, H. Vergin, G. R. Burmester and F. Buttgereit, “Nonsteroidal Antiinflammatory Drugs and a Selective Cyclooxygenase 2 Inhibitor Uncouple Mitochondria in Intact Cells,” Arthritis & Rheumatism, Vol. 48, No. 5, 2003, pp. 14381444. doi:10.1002/art.10969
[3]	M. Zanocchi, V. Tibaldi, D. Amati, F. Francisetti, E. Martinelli, M. Gonella, F. Cerrato, E. Ponte, A. Luppino, B. Bardelli, A. Canade, F. Gariglio, C. Moiraghi and M. Molaschi, “Adverse Drug Reactions as Cause of Visit to the Emergency Department: Incidence, Features and Outcomes,” Recenti Progressi in Medicina, Vol. 97, 2006, pp. 381-388.
[4]	G. Singh, “Triadafilopoulus G Epidemiology of NSAIDInduced GI Complications,” Journal of Rheumatology, Vol. 26 1999, pp. 18-24.
[5]	M. Filippa, M. I. Sancho and E. Gasull, “Encapsulation of Methyl and Ethyl Salicylates by Beta-Cyclodextrin HPLC, UV-Vis and Molecular Modeling Studies,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 48, No. 3, 2008, pp. 969-973. doi:10.1016/j.jpba.2008.06.005
[6]	T. Loftsson and D. Duchene, “Cyclodextrins and Their Pharmaceutical Applications,” International Journal of Pharmaceutics, Vol. 329, No. 1-2, 2007, pp. 1-11. doi:10.1016/j.ijpharm.2006.10.044
[7]	K. Miyake, H. Arima, F. Hirayama, M. Yamamoto, T. Horikawa, H. Sumiyoshi, S. Noda and K. Uekama, “Improvement of Solubility and Oral Bioavailability of Rutin by Complexation with 2-Hydroxypropyl-Beta-Cyclodextrin,” Pharmaceutical Development and Technology, Vol. 5, 2000, pp. 399-407.
[8]	K. Uekama, “Design and Evaluation of Cyclodextrin-Based Drug Formulation,” Chemical and Pharmaceutical Bulletin, Vol. 52, No. 8, 2004, pp. 900-915. doi:10.1248/cpb.52.900
[9]	R. Challa, A. Ahuja, J. Ali and R. K. Khar, “Cyclodextrins in Drug Delivery: An Updated Review,” AAPS PharmSciTech, Vol. 6, No. 2, 2005, pp. E329-E357. doi:10.1208/pt060243
[10]	T. Loftsson, S. B. Vogensen, M. E. Brewster and F. Konradsdottir, “Effects of Cyclodextrins on Drug Delivery through Biological Membranes,” Journal of Pharmaceutical Sciences, Vol. 96, No. 10, 2007, pp. 2532-2546. doi:10.1002/jps.20992
[11]	K. Uekama, F. Hirayama and H. J. Arima, “Recent Aspect of Cyclodextrin-Based Drug Delivery System,” Vol. 56, 2006, pp. 3-8.
[12]	M. A. Mintzer and E. E. Simanek, “Nonviral Vectors for Gene Delivery,” Chemical Reviews, Vol. 109, No. 2, 2009, pp. 259-302. doi:10.1021/cr800409e
[13]	M. Singh, R. Sharma and U. C. Banerjee, “Biotechnological Applications of Cyclodextrins,” Biotechnology Advances, Vol. 20, 2002, pp. 341-359.
[14]	V. J. Stella and R. A. Rajewski, “Cyclodextrins: Their Future in Drug Formulation and Delivery,” Pharm Res, Vol. 14, 1997, pp. 556-567. doi:10.1023/A:1012136608249
[15]	T. Loftsson, F. Konradsdottir and M. Masson, “Influence of Aqueous Diffusion Layer on Passive Drug Diffusion from Aqueous Cyclodextrin Solutions through Biological Membranes,” Pharmazie, Vol. 61, 2006, pp. 83-89.
[16]	T. J. Edkins, P. C. Meier, R. D. Shah, D. R. Bobbitt, H. Saranadasa and R. D. Lodevico, “Quantitative Analysis of Incomplete HPLC Resolution of Enantiomers. Fit of Polarimetric Detection for Dand L-Phenylalanine to a Gaussian Function,” Enantiomer, Vol. 7, No. 1, 2002, pp. 1122. doi:10.1080/10242430210703
[17]	M. F. Landoni and A. Soraci, “Pharmacology of Chiral Compounds: 2-Arylpropionic Acid Derivatives,” Current Drug Metabolism, Vol. 2, No. 1, 2001, pp. 37-51. doi:10.2174/1389200013338810
[18]	K. Lin, F. Zhang, S. Zhou, W. Liu, J. Gan and Z. Pan, “Stereoisomeric Separation and Toxicity of the Nematicide Fosthiazate,” Environmental Toxicology and Chemistry, Vol. 26, No. 11, 2007, pp. 2339-2344. doi:10.1897/07-255R.1
[19]	F. Jamali, R. Mehvar and F. M. Pasutto, “Enantioselective Aspects of Drug Action and Disposition: Therapeutic pitfalls,” Journal of Pharmaceutical Sciences, Vol. 78, No. 9, 1989, pp. 695-715. doi:10.1002/jps.2600780902
[20]	C.-J. Nunez-Agüero, C.-M. Escobar-Llanos, D. D?az, C. Jaime and R. Garduno-Juarez, “Chiral Discrimination of Ibuprofen Isomers in b-Cyclodextrin Inclusion Complexes: Experimental (NMR) and Theoretical (MD, MM/GBSA) Studies,” Tetrahedron, Vol. 62, No. 17, 2006, pp. 41624172. doi:10.1016/j.tet.2006.02.010
[21]	K. B. Lipkowitz, “Applications of Computational Chemistry to the Study of Cyclodextrins,” Chemical Reviews, Vol. 98, No. 5, 1998, pp. 1829-1874. doi:10.1021/cr9700179
[22]	Z. Gao and X. Zhao, “Enhancing Electrorheological Behaviors with Formation of β-Cyclodextrin Supramolecular Complex,” Polymer, Vol. 44, No. 16, 2003 pp. 45194526. doi:10.1016/S0032-3861(03)00416-6
[23]	J. Geczy, J. Bruhwyler, J. Scuvee-Moreau, V. Seutin, H. Masset, J. C. Van Heugen, A. Dresse, C. Lejeune, E. Decamp, L. Szente, J. Szejtli and J. F. Liegeois, “The Inclusion of Fluoxetine into Gamma-Cyclodextrin Increases Its Bioavailability: Behavioral, Electrophysiological and Pharmacokinetic Studies,” Psychopharmacology, Vol. 151, No. 4, 2000, pp. 328-334. doi:10.1007/s002130000512
[24]	F. Djedaini, S. Z. Lin, B. Perly and D. Wouessidjewe, “High-Field Nuclear Magnetic Resonance Techniques for the Investigation of a Beta-Cyclodextrin: Indomethacin Inclusion Complex,” Journal of Pharmaceutical Sciences, Vol. 79, No. 7, 1990, pp. 643-646. doi:10.1002/jps.2600790721
[25]	C. Yujuan and L. Runhua, “1H NMR Titration and Quantum Calculation for the Inclusion Complexes of cis-Cyclooctene, cis, cis-1, 3-Cyclooctadiene and cis, cis-1, 5-Cyclooctadiene with Beta-Cyclodextrin,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Vol. 73, No. 4, 2009, pp. 713-718. doi:10.1016/j.saa.2009.03.012
[26]	Y. Nievergelt, “Exact Equations for the equilibrium Constants of Single Intermolecular Complexes in Terms of Spectrophotometric Data,” Analyst, Vol. 119, No. 1, 1994, pp. 145-151. doi:10.1039/an9941900145
[27]	H. Fuchs and R. Gessner, “The Result of EquilibriumConstant Calculations Strongly Depends on the Evaluation Method Used and on the Type of Experimental Errors,” Biochemical Journal, Vol. 359, 2001, pp. 411-418. doi:10.1042/0264-6021:3590411
[28]	P. F. da Silva, J. C. Lima, A. A. Freitas, K. Shimizu, A. L. Macanita and F. H. Quina, “Charge-Transfer Complexation as a General Phenomenon in the Copigmentation of Anthocyanins,” Journal of Physical Chemistry A, Vol. 109, No. 32, 2005, pp. 7329-7338. doi:10.1021/jp052106s
[29]	N. Sadlej-Sosnowska, L. Gasinski and W. P. Oziminski, “Fluorometric Determination of Stability Constants of Inclusion Complexes of Naproxen and Charged Cyclodextrins in Aqueous Solutions. Nonlinear vs Linear Data Processing,” Polish Journal of Chemistry, Vol. 77, 2003 pp. 1039-1048.
[30]	K. A. Connors, “Optical Absorption Spectroscopy,” In: Ed., Binding Constants, The Measurement of Molecular Complex Stability, Wiley-Interscience, New York, 1987.
[31]	C. D. Tran, M. S. Baptista and T. Tomooka, “Determination of Binding Constants by Flow Injection Gradient Technique,” Langmuir, Vol. 14, No. 24, 1998 pp. 68866892. doi:10.1021/la9805894
[32]	Y. Ikeda, F. Hirayama, H. Arima, K. Uekama, Y. Yoshitake and K. Harano, “NMR Spectroscopic Characterization of Metoprolol/Cyclodextrin Complexes in Aqueous Solution: Cavity Size Dependency,” Journal of Pharmaceutical Sciences, Vol. 93, No. 7, 2004, pp. 1659-1671. doi:10.1002/jps.20077
[33]	E. Junquera, M. Martin-Pastor and E. Aicart, “Molecular Encapsulation of Flurbiprophen and/or Ibuprophen by Hydroxypropyl-b-Cyclodextrin in Aqueous Solution Potentiometric and Molecular Modelling Studies,” The Journal of Organic Chemistry, Vol. 63, 1998, pp. 43494358. doi:10.1021/jo980104g
[34]	P. Mura, S. Furlanetto, M. Cirri, F. Maestrelli, G. Corti and S. Pinzauti, “Interaction of Naproxen with Ionic Cyclodextrins in Aqueous Solution and in the Solid State,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 37, No. 5, 2005, pp. 987-994. doi:10.1016/j.jpba.2004.06.016
[35]	A. A. Dahab, D. El-Hag and A. F. Drake, “Simultaneous Determination of Photometric Accuracy during Circular Dichroism Measurements,” Analytical Methods, Vol. 2, No. 7, 2010, pp. 929-935. doi:10.1039/b9ay00216b
[36]	A. A. Dahab and D. El-Hag, “Rapid Analysis of NSAIDs Binding to b-Cyclodextrin Using the Simultaneous Measurement of Absorption and Circular Dichroism with a Novel Multi-Cell Low Volume Device,” Analytical and Bioanalytical Chemistry, Vol. 2012, pp.
[37]	K. Harata, “Induced Circular Dichroism of cycloamylose Complexes with Metaand Para-Disubstituted Benzenes,” Bioorganic Chemistry, Vol. 10, No. 3, 1981, pp. 255-265. doi:10.1016/0045-2068(81)90004-3
[38]	T. D. Thomas, “Acidity of Carboxylic Acids: Resonance Delocalization or Induction?” Journal of the Chemical Society, Perkin Transactions, Vol. 2, 1994, pp. 19451948.
[39]	J. B. Lambert, H. F. Shurvell, D. A. Lightner and R. G. Cooks, “Electronic Absorption and Chiroptical Spectroscopy,” In: J. Challice, Ed., Organic Structural Spectroscopy, Prentice Hall, New Jersey, 2001, pp. 274-303