Aqueous Solubility Enhancement of Mirtazapine: Effect of Cosolvent and Surfactant

Kenneth E. Ezealisiji¹, Chika J. Mbah^2*, Patience O. Osadebe²

¹Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, University of Port Harcourt, Port Harcourt, Nigeria.
²Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria.

DOI: 10.4236/pp.2015.610049                

Abstract

The poor aqueous solubility of drugs is a challenging problem faced by pharmaceutical scientists in drug formulation. Cosolvency and micellization techniques have been severally used to enhance the solubility of poorly aqueous soluble drugs. Mirtazapine, a tetracyclic antidepressant used for the treatment of moderate to severe depression and anxiety, has very poor aqueous solubility. The objective of the study was to investigate the effect of solubilizing agents (cosolvents and surfactants) on the aqueous solubility of mirtazapine while envisaging that any significant improvement in its aqueous solubility could contribute towards alleviating the withdrawal symptoms often associated with the drug. The solubility of mirtazapine was determined at room temperature in aqueous mixtures of cosolvents (propylene glycol and polyethylene glycol 400) and surfactants (polysorbate 20, polysorbate 80 and sodium lauryl sulfate). An exponential increase in mirtazapine solubility was observed when total drug solubility in water-cosolvent system was plotted against cosolvent fraction volume. Polyethylene glycol 400 gave larger solubilization capacity (σ) when compared to propylene glycol. With the surfactants, linear relationship between the total solubility of the drug in water-surfactant mixtures and surfactant concentration was noted. Sodium lauryl sulfate showed the largest solubilization power (k) when compared to the nonionic surfactants (polysorbate 20 and polysorbate 80 respectively). A linear relationship between standard free energy and partition coefficient was also observed. The result of the study shows that aqueous solubility of mirtazapine is significantly improved by cosolvency and micellization and therefore there exists the possibility of improving the withdrawal symptoms often experienced with the drug. It also suggests that large free energy is required for drugs with high partition coefficients to permeate the biological membrane.

Keywords

Mirtazapine, Cosolvency, Micellization, Aqueous Solubility

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Nakayama, K., Sakurai, T. and Katsu, H. (2004) Mirtazapine Increases Dopamine Release in Prefrontal Cortex by 5-HT1A Receptor Activation. Brain Research Bulletin, 63, 237-241. http://dx.doi.org/10.1016/j.brainresbull.2004.02.007
[2]	Peter, M. and Hartmann, S. (1999) Mirtazapine: A Newer Antidepressant. American Family Physician, 59, 159-161.
[3]	de Boer, T. (1996) The Pharmacology Profile of Mirtazapine. Journal of Clinical Psychiatry, 57, 19-25.
[4]	(2005) Physcian Desk Reference. 59th Edition, Thomson PDR, New Jersey, 2216.
[5]	Shafiq, S., Shakeel, F., Talegaonkar, S., Ahmed, F.J., Khar, R.K. and Ali, M. (2007) Development and Bioavailability Assessment of Ramipril Nanoemulsion Formulation. European Journal of Pharmaceutics and Biopharmaceutics, 66, 227-243. http://dx.doi.org/10.1016/j.ejpb.2006.10.014
[6]	Lee, P.J., Lenger, R. and Shestri, V.P. (2003) Novel Microemulsion Enhancer Formulation for Simultaneous Transdermal Delivery of Hydrophilic and Hydrophobic Drugs. Pharmaceutical Research, 20, 264-269. http://dx.doi.org/10.1023/A:1022283423116
[7]	Mbah, C.J. (2006) Solubilization of Valsartan by Aqueous Glycerol, Polyethylene Glycol and Micellar Solutions. Die Pharmazie, 61, 322-324.
[8]	Li, P., Zhao, L.W. and Yalkowsky, S.H. (1999) Combined Effect of Cosolvent and Cyclodextrin on Solubilization of Non-Polar Drugs. Journal of Pharmaceutical Sciences, 88, 1107-1111. http://dx.doi.org/10.1021/js990159d
[9]	Yalkowsky, S.H. and Roseman, T.J. (1981) Solubilization of Drugs by Co-Solvents. In: Yalkowsky, S.H., Ed., Techniques of Solubilization of Drugs, Vol. 12, Marcel Dekker Inc., New York, 91-134.
[10]	Yalkowsky, S.H. and Rubino, J.T. (1985) Solubilization of Cosolvents 1: Organic Solutes in Propylene Glycol-Water Mixtures. Journal of Pharmaceutical Sciences, 74, 416-421. http://dx.doi.org/10.1002/jps.2600740410
[11]	Seedher, N. and Kaur, J. (2003) Solubilization of Nimesulide: Use of Co-Solvents. Indian Journal of Pharmaceutical Sciences, 65, 58-61.
[12]	Krishn, A.K. and Flanagan, D.R. (1989) Micellar Solubilization of a New Antimalarial Drug, β-Arteether. Journal of Pharmaceutical Sciences, 78, 574-576. http://dx.doi.org/10.1002/jps.2600780713
[13]	Zhao, L., Li, P. and Yalkowsky, S.H. (1999) Solubilization of Fluasterone. Journal of Pharmaceutical Sciences, 88, 967-969. http://dx.doi.org/10.1021/js9901413
[14]	Li, P. and Zhao, L. (2003) Solubilization of Flurbiprofen in pH-Surfactant Solutions. Journal of Pharmaceutical Sciences, 92, 951-956. http://dx.doi.org/10.1002/jps.10360
[15]	Alkhamis, K.A., Allaboun, H. and Al-Momani, W.Y. (2003) Study of the Solubilization of Gliclazide by Aqueous Micellar Solutions. Journal of Pharmaceutical Sciences, 92, 839-846. http://dx.doi.org/10.1002/jps.10350
[16]	Seedher, N. and Kanojia, M. (2008) Micellar Solubilization of Some Poorly Soluble Antidiabetic Drugs. AAPS Pharm SciTech, 9, 431-436. http://dx.doi.org/10.1208/s12249-008-9057-5
[17]	Hunter, R.J. (1993) Introduction to Modern Colloid Science. Oxford University Press, Oxford.
[18]	Zhao, L., Li, P. and Yalkowsky, S.H. (1999) Solubilization of Fluasterone. Journal of Pharmaceutical Sciences, 88, 967-969. http://dx.doi.org/10.1021/js9901413
[19]	Ran, Y., Zhao, L., Xu, Q. and Yalkowsky, H. (2001) Solubilization of Cyclosporin A. AAPS PharmSciTech, 2, 23-26. http://dx.doi.org/10.1208/pt020102
[20]	Ong, J.T.H. and Manoukian, E. (1988) Micellar Solubilization of Timbesone Acetate in Aqueous and Aqueous Propy-lene Glycol Solutions of Nonionic Surfactants. Pharmaceutical Research, 3, 704-708. http://dx.doi.org/10.1023/A:1015903827042
[21]	Rangel-Yagui, C.O., Junior, A.P. and Tavares, L.C. (2005) Micellar Solubilization of Drugs. Journal of Pharmaceutical Sciences, 8, 147-163.
[22]	Sweetana, S. and Akers, M.J. (1996) Solubility Principles and Practices for Parenteral Drug Dosage form Development. PDA Journal of Pharmaceutical Science and Technology, 50, 50-56.
[23]	Powell, M.J., Nguyen, T. and Baloian, L. (1998) Compendium of Excipients for Parenteral Formulations. PDA Journal of Pharmaceutical Science and Technology, 52, 238-311.
[24]	Mottu, F., Laurent, A., Rufenacht, D. and Doelker, E. (2000) Organic Solvents for Pharmaceutical Parenterals and Embolic Liquids: A Review of Toxicity Data. PDA Journal of Pharmaceutical Science and Technology, 54, 456-469.