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Interaction of Surface Active Drug Promethazine Hydrochloride with Surfactants: Drug Release from Microemulsions

Wechselwirkung des oberflächenaktiven Wirkstoffs Promethazinhydrochlorid mit Tensiden: Wirkstofffreisetzung aus Mikroemulsionen
Manoni Kurtanidze, Tinatin Butkhuzi, Irma Tikanadze, Rusudan Chaladze, Manuchar Gvaramia, Ketevan Nanobashvili, Maka Alexishvili, Polina Toidze and Marina Rukhadze


The interaction of surface-active drugs with surfactants, used in the simulation of artificial membranes by direct and reversed micelles, mainly determines the transport of drugs in the body and the complex process of the binding to receptors. Besides, the delivery of drugs into the body via microemulsions has been successfully used to reduce the first-pass metabolism. The structure of mixed reverse microemulsions based on the ionic surfactant sodium bis(2-ethylhexyl)sulfosuccinate (AOT) and the cationic surface active drug promethazine hydrochloride (PMT) was studied spectroscopically in the infrared and UV-visible regions, as well as using electrical conductivity and dynamic light scattering. The release profile of PMT from AOT-based microemulsions was studied using cellulose dialysis bags. The introduction of PMT additive into the water pockets of reverse AOT micelles leads to: a) an increase in free water fraction and a decrease in bound water fraction; b) changing the chromatographic retention factors of the model compounds; c) insignificant influence on the values of the binding constant of optical probe o-nitroaniline with the head groups of AOT; d) quenching of water-induced percolation in electrical conductance of reverse AOT microemulsions; e) a slight decrease in the size of water droplets at the same values of the molar ratio of water/surfactant. The release of PMT from the aqueous system obeys Fick’s law of diffusion (n = 0.4852), and the release of PMT from microemulsions is based on non-Fickian or anomalous diffusion.


Die Wechselwirkung von oberflächenaktiven Arzneimitteln mit Tensiden, die bei der Simulation künstlicher Membranen durch direkte und umgekehrte Mizellen verwendet wurden, bestimmt hauptsächlich den Transport von Arzneimitteln im Körper und den komplexen Prozess ihrer Bindung an Rezeptoren. Außerdem wurde die Abgabe von Arzneimitteln in den Körper durch Mikroemulsionen erfolgreich für die Reduzierung des First-Pass-Metabolismus verwendet. Die Struktur von gemischten Umkehrmikroemulsionen auf der Basis des ionischen Tensids Natrium-bis-(2-ethylhexyl)-sulfosuccinat (AOT) und des kationischen oberflächenaktiven Arzneimittels Promethazinhydrochlorid (PMT) wurde spektroskopisch im infraroten und UV-sichtbaren Bereich sowie mit Methoden der elektrische Leitfähigkeit und dynamische Lichtstreuung untersucht. Das Freisetzungsprofil von PMT aus AOT-basierten Mikroemulsionen wurde unter Verwendung von Cellulosedialysebeuteln untersucht. Die Einführung von PMT-Additiven in die Wassertaschen von AOT-Umkehrmizellen führt zu: a) einer Zunahme der freien Wasserfraktion und einer Abnahme der gebundenen Wasserfraktion; b) einer Änderung der chromatographischen Retentionsfaktoren der Modellverbindungen; c) einen unbedeutenden Einfluss auf die Werte der Bindungskonstante der optischen Sonde o-Nitroanilin mit den Kopfgruppen von AOT; d) dem Löschen der wasserinduzierten Perkolation in der elektrischen Leitfähigkeit von umgekehrten AOT-Mikroemulsionen; e) einer leichten Abnahme der Größe der Wassertröpfchen bei den gleichen Werten des Molverhältnisses von Wasser/Tensid. Die Freisetzung von PMT aus dem wässrigen System folgt dem Fick‘schen Diffusionsgesetz (n = 0,4852), und die Freisetzung von PMT aus Mikroemulsionen basiert auf einer nicht-Fick‘schen oder anomalen Diffusion.

Prof. Marina Rukhadze 3, I.Chavchavadze ave Tbilisi, 0179 Georgia Tel.: +995 599 19 75 25


This work was supported by Shota Rustaveli National Science Foundation of Georgia (SRNSFG) [YS-18-1940].


1 Schreier, S., Malheiros, S. V. P. and Paula, E.: Surface active drugs: self-association and interaction with membranes and surfactants, Biochimica & Biophysica Acta (BBA) – Biomembranes. 1508 (2000) 210–234. DOI:10.1016/S0304-4157(00)00012-5 Search in Google Scholar

2 Mahajan, S. and Mahajan, R. K.: Interaction of phenothaizine drugs with surfactants: A detailed physicochemical overview, Advances in Colloid and Interface Science. 199–200 (2013) 1–14. PMid:23933135; DOI:10.1016/j.cis.2013.06.008 Search in Google Scholar

3 Florence, A. S.: Biological significance of micelle formation. In: Micellization, solubilization and microemulsions. (ed. Mittal K.L.), Moscow: Mir, 1980 (Russian Translation) 43–62. DOI: N/A. Search in Google Scholar

4 Attwood, D., Florence, A. T. and Gillan, J. M. N.: Micellar properties of drugs: Properties of Micellar Aggregates of Phenothiazines and Their Aqueous Solutions, Journal of Pharmaceutical Sciences. 63 (1974) 988–993. PMid:4853206; DOI:10.1002/jps.2600630649 Search in Google Scholar

5 Florence, T. A. and Gillan, J. M. N.: Biological implications of the use of surfactants in medicine: and biphasic effects of surfactants in biological systems, Pestic. Sci. 6 (1975) 429–439. DOI:10.1002/ps.2780060411 Search in Google Scholar

6 Attwood, D.: Micellar, Drugs. Encyclopedia of Surface and Colloid Science, Hubbard, A, (ed) Marcel Dekker Inc., NY, (2002) 3370–3385. DOI: N/A. Search in Google Scholar

7 Anderson, N. and Borlak, J.: Drug-induced phospholipidosis. FEBS Letters, 580 (2006) 5533–5540. PMid:16979167; DOI:10.1016/j.febslet.2006.08.061 Search in Google Scholar

8 Carey, C. M., Hirom, P. C. and Small, M. D.: A study of physicochemical interactions between biliary lipids and chlorpromazine hydrochloride, Biochem J. 153 (1976) 519–531. PMid:821466; DOI:10.1042/bj1530519 Search in Google Scholar

9 Rub, M. A., Khan, F., Kumar, D. and Asiri, A. M.: Study of Mixed Micelles of Promethazine Hydrochloride (PMT) and Nonionic Surfactant (TX-100) Mixtures at different Temperatures and Compositions, Tenside Surf. Det. 52 (2015) 236–244. DOI:10.3139/113.110371 Search in Google Scholar

10 Narang, A. S., Delmarre, D. and Gao, D.: Stable drug encapsulation in micelles and microemulsions, International Journals of Pharmaceutics 345 (2007) 9–25. PMid:17945446; DOI:10.1016/j.ijpharm.2007.08.057 Search in Google Scholar

11 Jha, S. K., Dey, S. and Karki, R.: Microemulsions- Potential Carrier for Improved Drug Delivery. Asian Journal of Biomedical and Pharmaceutical Sciences. 1 (2011) 5–9. DOI: N/A. Search in Google Scholar

12 Bagwe, R. P., Kanicky, J. R., Palla, B. J., Patanjali, P. K. and Shah, D.: Improved Drug Delivery Using Microemulsions: Rationale, Recent Progress, and New Horizons. Critical Reviews in Therapeutic Drug Carrier Systems 18 (2001) 77–140. DOI:10.1615/CritRevTherDrugCarrierSyst.v18.i1.20 Search in Google Scholar

13 Dahan, A. and Hoffman A.: Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs, European Journal of Pharmaceutical Sciences 24 (2005) 381–388. PMid:15734305; DOI:10.1016/j.ejps.2004.12.006 Search in Google Scholar

14 Caliph, S. M., Charman, W. N. and Porrer, C. J. H.: Effect of short, medium and long-chain fatty acid-based vehicles on the absolute oral bioavailibility and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J. Pharm. Sci. 89 (2000) 1073–84. DOI:10.1002/1520-6017(200008)89:°<1073:aid-jps12>;2-v Search in Google Scholar

15 Thakkar, H., Nangesh, J., Parmar, M. and Patel, D.: Formulation and Characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery systems, Journal of Pharmacy and Bioallied Sciences. 3 (2011) 442–448. PMid:21966167; DOI:10.4103/0975-7406.84463 Search in Google Scholar

16 Washington, C.: Drug release from microdisperse systems: a critical review. International Journal of pharmaceutics. 58 (1990) 1–12. DOI:10.1016/0378-5173(90)90280-H Search in Google Scholar

17 Dash, S., Murthy, P. N., Nath, L. and Chowdhury, P.: Kinetic Modeling on Drug Release From Controlled Drug Delivery Systems. Acta Poloniae Pharmaceutica – Drug Research. 67 (2010) 217–223. DOI: N/A. Search in Google Scholar

18 Gouda, R., Baishya, H. and Qing, Z.: Application of Methematical Models in Drug release Kinetics of Carbidopa and Levodpoa ER Tablets, Journal of Developing Drugs. 6 (2017) 1–8. DOI:10.4172/2329-6631.1000171 Search in Google Scholar

19 Mehta, S. K., Kaur, G. and Bhasin, K. K.: Analysis of Tween based microemulsion in the presence of TB drug rifampicin. Colloids and Surfaces B: Biointerfaces 60 (2007) 95–104. PMid:17646089; DOI:10.1016/j.colsurfb.2007.06.012 Search in Google Scholar

20 Kelmann, R. G., Kuminek, G., Teixeira, H. F. and Koester, L. S.: Carbamazepine parenteral nanoemulsions prepared by spontaneous emulsification process. International Journal of Pharmaceutics. 342 (2007) 231–239. PMid:17582711; DOI:10.1016/j.ijpharm.2007.05.004 Search in Google Scholar

21 Mehta, S. K., Kaur, G. and Bhasin, K. K.: Tween-Embedded Microemulsions – Physicochemical and Spectroscopic Analysis for Antitubercular Drugs. AAPS PharmSciTech. 11 (2010) 143–153. PMid:20087697; DOI:10.1208/s12249-009-9356-5 Search in Google Scholar

22 Guo, R., Qian, S., Zhu, J. and Qian, J.: The release of cephanone in CTAB/n-C5H11OH/H2O system. Colloid Polym Sci. 284 (2006) 468–474. DOI:10.1007/S00396-005-1336-Z Search in Google Scholar

23 Gupta, R. R. and Jain, S. K.: Varshney M. AOT water-in-oil microemulsions as a penetration enhancer in transdermal drug delivery of 5-fluorouracil. Colloids and Surfaces B: Biointerfaces. 41 (2005) 25–32. PMid:15698753; DOI:10.1016/j.colsurfb.2004.09.008 Search in Google Scholar

24 Trotta, M., Gasco, M. R. and Morel, S.: Release of Drugs from Oil-Water Microemulsions. Journal of controlled release. 10 (1989) 237–243. DOI:10.1016/0168-3659(89)90073-4 Search in Google Scholar

25 Kumar, D. and Rub, M. A.: Effect of anionic surfactant and temperature on micellization behavior of promethazine hydrochloride drug in absence and presence of urea. Journal of molecular liquids. 238 (2017) 389–396. DOI:10.1016/j.molliq.2017.05.027 Search in Google Scholar

26 Din, K., Rub, M. A. and Naqvi, A. Z.: Mixed micelles of amphiphilic drug promethazine hydrochloride and surfactants (conventional and gemini) at 293.15 K to 308.15 K: Composition, interaction and stability of the aggregates. Journal of colloids and Interface Science. 354 (2011) 700–708. PMid:21134682; DOI:10.1016/j.jcis.2010.11.005 Search in Google Scholar

27 Khan, A. B., Ali, M., Dohare, N., Singh, P. and Patel, R.: Micellization behavior of the amphiphilic drug promethazine hydrochloride with 1-decyl-3-methylimidazolium chloride and its thermodynamic characteristics. Journal of molecular liquids. 198 (2014) 341–346. DOI:10.1016/j.molliq.2014.07.021 Search in Google Scholar

28 Mahajan, R. K., Mahajan, S. and Bhadani, A.: Singh S. Physicochemical studies of pyridinium gemini surfactants with promethazine hydrochloride in aqueous solution. Phys. Chem. Chem. Phys. 14 (2012) 887–898. PMid:22119804; DOI:10.1039/C1CP22448D Search in Google Scholar

29 Rukhadze, M., Alexishvili, M., Gonashvili, M. and Sebiskveradze, M.: Interaction of surface-active drugs in rabbits. Biomedical Chromatography. 19 (2005) 123–128. PMid:15473013; DOI:10.1002/bmc.427 Search in Google Scholar

30 Kokiashvili, N., Alexishvili, M., Gonashvili, M., Okujava, N., Titvinidze, G. and Rukhadze, M.: Revealing of pharmacokinetic peculiarities of surface active drug promethazine in its interaction with caffeine in rabbits. Colloids and Surfaces A: Physicochem. Eng. Aspects. 413 (2012) 169–173. DOI:10.1016/j.colsurfa.2011.12.061 Search in Google Scholar

31 Butkhuzi, T., Chaladze, R., Lominadze, N., Rukhadze, M., Gvaramia, M., Kurtanidze, M., Bezarashvili, G. and Sigua, K.: Study of influence of ionic additives to AOT reverse microemulsions by liquid chromatography, IR and UV–visible spectroscopy. Colloids and Surfaces A: Physicochem. Eng. Aspects. 442 (2014) 98–104. DOI:10.1016/j.colsurfa.2013.03.001 Search in Google Scholar

32 Tikanadze, I., Kurtanidze, M., Rukhadze, M., Nanobashvili, K., Toidze, P., Bezarashvili, G. and Sigua, K.: Structure of Mixed Reverse Microemulsions Based on Sodium Bis (2-ethylhexyl) Sulfosuccinate and Sodium Cholate. Journal of Surfactants and Detergents. 23 (2020) 339–346. DOI:10.1002/jsde.12381 Search in Google Scholar

33 Correa, N. M. and Silber, J. J.: Binding of Nitroanilines to Reverse Micelles of AOT n-Hexane. J Mol Liq. 72 (1997) 163–176. DOI:10.1016/S0167-7322(97)00037-8 Search in Google Scholar

34 Falcone, R. D., Silber, J. J., Biasutti, M. A. and Correa, N. M.: Binding of o-Nitroaniline to Nonaqueous AOT Reverse Micelles. Organic Chemistry in Argentina, ARKIVOC. vii (2011) 369–379. DOI:10.3998/ark.5550190.0012.730 Search in Google Scholar

35 Saif, M. J. and Anwar, J. A.: new spectrophotometric method for the determination of promethazine-HCl from pure and pharmaceutical preparations. Talanta 67 (2005) 869–872. PMid:18970252; DOI:10.1016/j.talanta.2005.03.034 Search in Google Scholar

36 Jain, T. K., Varshney, M. and Maitra, A.: Structural Studies of Aerosol OT Reverse Micellar Aggregates by FT-IR Spectroscopy, J. Phys. Chem. 93 (1989) 7409–7416. DOI:10.1021/j100358a032 Search in Google Scholar

37 Altria, K., Broderick, M., Donegan, S. and Power, J.: Preliminary Study on the Use of Water-in-Oil Microemulsion Eluents in HPLC, Chromatographia. 62 (2005) 341–348. DOI:10.1365/S10337-005-0630-8 Search in Google Scholar

Received: 2021-01-31
Accepted: 2021-06-18
Published Online: 2021-09-25
Published in Print: 2021-09-30

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