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Preparation and Characterization of Flurbiprofen/β-Cyclodextrin Inclusion Complex

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This study aims to ameliorate the water solubility of flurbiprofen by using β-cyclodextrin (β-CD). The drug/ligand 1:1 (M/M) stoichiometry was determined based on the effect of β-CD on the solubility of flurbiprofen. Several methods of preparing flurbiprofen/β-CD inclusion complex were investigated and a solvent method using hot water to dissolve the starting materials was selected. The selected method showed a lot of advantages such as high complexing ability, good product yield, simple and eco-friendly process. The obtained product was characterized using various analytical techniques such as high-performance liquid chromatography, differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy. The product had a predominantly amorphous form with clathrate particles of about 2-7 µm in size, irregular edges and rough surfaces. The study results show that in the complexing process, flurbiprofen replaced water molecules located in the conical cavity of β-CD. The complex contained 19.91% flurbiprofen by mass with water solubility at 37°C was 1,100 µg/ml. The results also show that the complexing with β-CD significantly improved the water solubility of flurbiprofen by both speed and level. Keywords Flurbiprofen, β-cyclodextrin, inclusion complex, water solubility, preparation, characterization. References [1] K. Maroof, F. Zafar, H. Ali, S. Naveed, Flurbiprofen: a potent pain reliever, J. Bioequiv. Availab. 7(1) (2015) 056-058. https://doi.org/10.4172/jbb.1000214.[2] J.J. Thebault, G. Lagrue, C.E. Blatrix, L. Cheynier, R. Cluzan, Clinical pharmacology of flurbiprofen: a novel inhibitor of platelet aggregation, Curr. Med. Res. Opin. 5(1) (1977) 130-134. https://doi.org/10.1185/03007997709108990.[3] H. Geerts, Drug evaluation: (R)-flurbiprofen - an enantiomer of flurbiprofen for the treatment of Alzheimer's disease, Idrugs. 10(2) (2007) 121-133.[4] P.L. McGeer, M. Schulzer, E.G. McGeer, Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies, Neurology. 47(2) (1996) 425-432. https://doi.org/10.1212/WNL.47.2.425.[5] S. Meister, I. Zlatev, J. Stab, D. Docter, S. Baches, et al., Nanoparticulate flurbiprofen reduces amyloid-β 42 generation in an in vitro blood-brain barrier model, Alzheimers Res. Ther. 5(6) (2013) 51-63. https://doi.org/10.1186/alzrt225.[6] K.P. Townsend, D. Praticò, Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs, FASEB J. 19(12) (2005) 1592-1601. https://doi.org/10.1096/fj.04-3620rev.[7] C.K. Kim, Y.S. Yoon, J.Y. Kong, Preparation and evaluation of flurbiprofen dry elixir as a novel dosage form using a spray-drying technique, Int. J. Pharm. 120 (1995) 21-31. https://doi.org/10.1016/0378-5173(94)00375-F.[8] M.J. Habib, M.T. Phan, G. Owusu-Ababio, Dissolution profiles of flurbiprofen in phospholipid solid dispersions, Drug Dev. Ind. Pharm. 24 (1998) 1077-1082. https://doi.org/10.3109/03639049809089952.[9] D.H. Oh, Y.J. Park, J.H. Kang, C.S. Yong, H.G. Choi, Physicochemical characterization and in vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline change, Drug. Deliv. 18 (2010) 46-53. https://doi.org/10.3109/10717544.2010.509365.[10] G.D. Gupta, S. Jain, N.K. Jain, Formulation of an aqueous injection of flurbiprofen, Pharmazie. 52 (1997) 709-712. https://doi.org/10.1080/10826079708005547.[11] K.W. Ambade, S.L. Jadhav, M.N. Gambhire, S.D. Kurmi, V.J. Kadam, K.R. Jadhav, Formulation and evaluation of flurbiprofen microemulsion, Curr. Drug Deliv. 5 (2008) 32–41[12] H.H. Baek, S.Y. Kwon, S.J. Rho, W.S. Lee, H.J. Yang, J.M. Hah, H.G. Choi, Y.R. Kim, C.S. Yong, Enhanced solubility and bioavailability of flurbiprofen by cycloamylose, Arch. Pharm. Res. 34 (2011) 391-397. https://doi.org/10.1007/s12272-011-0306-x.[13] A. Muraoka, T. Tokumura, Y. Machida, Evaluation of the bioavailability of flurbiprofen and its β-cyclodextrin inclusion complex in four different doses upon oral administration to rats, Eur. J. Pharm. Biopharm. 58(3) (2004) 667-671. https://doi.org/10.1016/j.ejpb.2004.03.030.[14] T. Tokumura, A. Muraoka, Y. Machida, Improvement of oral bioavailability of flurbiprofen from flurbiprofen/beta-cyclodextrin inclusion complex by action of cinnarizine, Eur. J. Pharm. Biopharm. 73 (2009) 202-204. https://doi.org/10.1016/j.ejpb.2009.04.018.[15] D. Li, M. Han, P. Balakrishnan, Y. Yan, D. Oh, et al., Enhanced oral bioavailability of flurbiprofen by combined use of micelle solution and inclusion compound, Arch. Pharm. Res. 33(1) (2010) 95-101. https://doi.org/10.1007/s12272-010-2231-9.[16] H. Arima, K. Motoyama, T. Irie, Recent findings on safety profiles of cyclodextrins, cyclodextrin conjugates, and polypseudorotaxanes, in: E. Bilensoy (Ed.), Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedicine: Current and Future Industrial Applications, John Wiley & Sons Inc., Hoboken, 2011, pp. 91-122. https://doi.org/10.1002/9780470926819.ch5.[17] T.J. Grattan, Inclusion complexes of beta-cyclodextrin with flurbiprofen, ketoprofen and naproxen, International patent WO1995007104A1, March 16, 1995.[18] M. Cirri, C. Rangoni, F. Maestrelli, G. Corti, P. Mura, Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes, Drug Dev. Ind. Pharm. 31(7) (2005) 697-707. https://doi.org/10.1080/03639040500253694.[19] M. Tirunagari, N. Mehveen, M.F. Qureshi, J.P. Sultana, V. Tirunagari (2012), Solubility Enhancement of Flurbiprofen using Different Solubilization Techniques, Int. J. Pharm. Pharm. Sci. 4(4) (2012) 97-100.[20] P. Saokham, C. Muankaew, P. Jansook, T. Loftsson, Solubility of cyclodextrins and drug/cyclodextrin complexes, Molecules. 23(5) (2018) 1161-1175. https://doi.org/10.3390/molecules23051161.[21] S. Pereva, T. Sarafska, S. Bogdanova, T. Spassov, Efficiency of “cyclodextrin-ibuprofen” inclusion complex formation, J. Drug Deliv. Sci. Tec. 35 (2016) 34-39. https://doi.org/10.1016/j.jddst.2016.04.006.[22] T.T.B. Nguyen, N.A. Dang, M.A. Tran, T.H. Nguyen, Validation of a high-performance liquid chromatographic method with diod array detection for the quantification of flurbiprofen in 100 mg film-coated tablet, VNU Journal of Science: Medical and Pharmaceutical Sciences. 33(2) (2017) 41-49. https://doi.org/10.25073/2588-1132/vnumps.4085.[23] T. Higuchi, K.A. Connors, Phase-solubility techniques, Adv. Anal. Chem. Instrum. 4 (1965) 117-122.    
Title: Preparation and Characterization of Flurbiprofen/β-Cyclodextrin Inclusion Complex
Description:
This study aims to ameliorate the water solubility of flurbiprofen by using β-cyclodextrin (β-CD).
The drug/ligand 1:1 (M/M) stoichiometry was determined based on the effect of β-CD on the solubility of flurbiprofen.
Several methods of preparing flurbiprofen/β-CD inclusion complex were investigated and a solvent method using hot water to dissolve the starting materials was selected.
The selected method showed a lot of advantages such as high complexing ability, good product yield, simple and eco-friendly process.
The obtained product was characterized using various analytical techniques such as high-performance liquid chromatography, differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy.
The product had a predominantly amorphous form with clathrate particles of about 2-7 µm in size, irregular edges and rough surfaces.
The study results show that in the complexing process, flurbiprofen replaced water molecules located in the conical cavity of β-CD.
The complex contained 19.
91% flurbiprofen by mass with water solubility at 37°C was 1,100 µg/ml.
The results also show that the complexing with β-CD significantly improved the water solubility of flurbiprofen by both speed and level.
Keywords Flurbiprofen, β-cyclodextrin, inclusion complex, water solubility, preparation, characterization.
References [1] K.
Maroof, F.
Zafar, H.
Ali, S.
Naveed, Flurbiprofen: a potent pain reliever, J.
Bioequiv.
Availab.
7(1) (2015) 056-058.
https://doi.
org/10.
4172/jbb.
1000214.
[2] J.
J.
Thebault, G.
Lagrue, C.
E.
Blatrix, L.
Cheynier, R.
Cluzan, Clinical pharmacology of flurbiprofen: a novel inhibitor of platelet aggregation, Curr.
Med.
Res.
Opin.
5(1) (1977) 130-134.
https://doi.
org/10.
1185/03007997709108990.
[3] H.
Geerts, Drug evaluation: (R)-flurbiprofen - an enantiomer of flurbiprofen for the treatment of Alzheimer's disease, Idrugs.
10(2) (2007) 121-133.
[4] P.
L.
McGeer, M.
Schulzer, E.
G.
McGeer, Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies, Neurology.
47(2) (1996) 425-432.
https://doi.
org/10.
1212/WNL.
47.
2.
425.
[5] S.
Meister, I.
Zlatev, J.
Stab, D.
Docter, S.
Baches, et al.
, Nanoparticulate flurbiprofen reduces amyloid-β 42 generation in an in vitro blood-brain barrier model, Alzheimers Res.
Ther.
5(6) (2013) 51-63.
https://doi.
org/10.
1186/alzrt225.
[6] K.
P.
Townsend, D.
Praticò, Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs, FASEB J.
19(12) (2005) 1592-1601.
https://doi.
org/10.
1096/fj.
04-3620rev.
[7] C.
K.
Kim, Y.
S.
Yoon, J.
Y.
Kong, Preparation and evaluation of flurbiprofen dry elixir as a novel dosage form using a spray-drying technique, Int.
J.
Pharm.
120 (1995) 21-31.
https://doi.
org/10.
1016/0378-5173(94)00375-F.
[8] M.
J.
Habib, M.
T.
Phan, G.
Owusu-Ababio, Dissolution profiles of flurbiprofen in phospholipid solid dispersions, Drug Dev.
Ind.
Pharm.
24 (1998) 1077-1082.
https://doi.
org/10.
3109/03639049809089952.
[9] D.
H.
Oh, Y.
J.
Park, J.
H.
Kang, C.
S.
Yong, H.
G.
Choi, Physicochemical characterization and in vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline change, Drug.
Deliv.
18 (2010) 46-53.
https://doi.
org/10.
3109/10717544.
2010.
509365.
[10] G.
D.
Gupta, S.
Jain, N.
K.
Jain, Formulation of an aqueous injection of flurbiprofen, Pharmazie.
52 (1997) 709-712.
https://doi.
org/10.
1080/10826079708005547.
[11] K.
W.
Ambade, S.
L.
Jadhav, M.
N.
Gambhire, S.
D.
Kurmi, V.
J.
Kadam, K.
R.
Jadhav, Formulation and evaluation of flurbiprofen microemulsion, Curr.
Drug Deliv.
5 (2008) 32–41[12] H.
H.
Baek, S.
Y.
Kwon, S.
J.
Rho, W.
S.
Lee, H.
J.
Yang, J.
M.
Hah, H.
G.
Choi, Y.
R.
Kim, C.
S.
Yong, Enhanced solubility and bioavailability of flurbiprofen by cycloamylose, Arch.
Pharm.
Res.
34 (2011) 391-397.
https://doi.
org/10.
1007/s12272-011-0306-x.
[13] A.
Muraoka, T.
Tokumura, Y.
Machida, Evaluation of the bioavailability of flurbiprofen and its β-cyclodextrin inclusion complex in four different doses upon oral administration to rats, Eur.
J.
Pharm.
Biopharm.
58(3) (2004) 667-671.
https://doi.
org/10.
1016/j.
ejpb.
2004.
03.
030.
[14] T.
Tokumura, A.
Muraoka, Y.
Machida, Improvement of oral bioavailability of flurbiprofen from flurbiprofen/beta-cyclodextrin inclusion complex by action of cinnarizine, Eur.
J.
Pharm.
Biopharm.
73 (2009) 202-204.
https://doi.
org/10.
1016/j.
ejpb.
2009.
04.
018.
[15] D.
Li, M.
Han, P.
Balakrishnan, Y.
Yan, D.
Oh, et al.
, Enhanced oral bioavailability of flurbiprofen by combined use of micelle solution and inclusion compound, Arch.
Pharm.
Res.
33(1) (2010) 95-101.
https://doi.
org/10.
1007/s12272-010-2231-9.
[16] H.
Arima, K.
Motoyama, T.
Irie, Recent findings on safety profiles of cyclodextrins, cyclodextrin conjugates, and polypseudorotaxanes, in: E.
Bilensoy (Ed.
), Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedicine: Current and Future Industrial Applications, John Wiley & Sons Inc.
, Hoboken, 2011, pp.
91-122.
https://doi.
org/10.
1002/9780470926819.
ch5.
[17] T.
J.
Grattan, Inclusion complexes of beta-cyclodextrin with flurbiprofen, ketoprofen and naproxen, International patent WO1995007104A1, March 16, 1995.
[18] M.
Cirri, C.
Rangoni, F.
Maestrelli, G.
Corti, P.
Mura, Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes, Drug Dev.
Ind.
Pharm.
31(7) (2005) 697-707.
https://doi.
org/10.
1080/03639040500253694.
[19] M.
Tirunagari, N.
Mehveen, M.
F.
Qureshi, J.
P.
Sultana, V.
Tirunagari (2012), Solubility Enhancement of Flurbiprofen using Different Solubilization Techniques, Int.
J.
Pharm.
Pharm.
Sci.
4(4) (2012) 97-100.
[20] P.
Saokham, C.
Muankaew, P.
Jansook, T.
Loftsson, Solubility of cyclodextrins and drug/cyclodextrin complexes, Molecules.
23(5) (2018) 1161-1175.
https://doi.
org/10.
3390/molecules23051161.
[21] S.
Pereva, T.
Sarafska, S.
Bogdanova, T.
Spassov, Efficiency of “cyclodextrin-ibuprofen” inclusion complex formation, J.
Drug Deliv.
Sci.
Tec.
35 (2016) 34-39.
https://doi.
org/10.
1016/j.
jddst.
2016.
04.
006.
[22] T.
T.
B.
Nguyen, N.
A.
Dang, M.
A.
Tran, T.
H.
Nguyen, Validation of a high-performance liquid chromatographic method with diod array detection for the quantification of flurbiprofen in 100 mg film-coated tablet, VNU Journal of Science: Medical and Pharmaceutical Sciences.
33(2) (2017) 41-49.
https://doi.
org/10.
25073/2588-1132/vnumps.
4085.
[23] T.
Higuchi, K.
A.
Connors, Phase-solubility techniques, Adv.
Anal.
Chem.
Instrum.
4 (1965) 117-122.
   .

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