Sabyasachi Banerjee, K Ravi Shankar, Y Prasad Rajendra


Arrhythmia follows chronobiology, thus necessitating development of time-dependent formulation for its treatment. The aim of the current work was to develop a solubility-enhanced chronotherapeutic system of felodipine, a widely prescribed anti-arrhythmic. Systematically optimized hot-melt extrusion process was employed to formulate solubility-enhanced extrudates. Film-casting method was adopted for the selection of polymers. Drug released at 5, 15, 30min was taken as response variables in 32 face-centered cube design. Nearly 10-fold increase was observed in the solubility of the optimized extrudates in comparison to pure drug. Physical characterization of the extrudates depicted complete amorphization of drug. Sequential coating was performed on to the extrudates to enable a time-dependent release. In-vitro studies clearly demonstrated that 25% of drug was available rapidly within 10 min of administration. The remaining 75% of drug was available over a period of 4, 8 and 12h. Stability studies performed for 6 months at accelerated conditions depicted no significant change in the physicochemical characteristics of the optimized formulation. In-vivo pharmacokinetic studies conducted in beagle dogs ratified the results of in-vitro studies where a sequential time dependent absorption of felodipine was observed over a period of 12h. Concisely, the studies demonstrated successful development of solubility-enhanced chronotherapeutic system of felodipine.


hot-melt; central composite design; pharmacokinetics; arrhythmia; extrudates

Full Text:

PDF (41-52)


Abdul, S., Chandewar, A.V. and Jaiswal, S.B., 2010. A flexible technology for modified-release drugs: multiple-unit pellet system (MUPS). J Control Release. 147: 2-16.

Alavi, A.K., Squillante, E., and Mehta, K.A., 2002. Formulation of enterosoluble microparticles for an acid labile protein. J Pharm Pharm Sci. 5: 234-44.

Alonzo, D.E., Gao, Y., Zhou, D., Mo, H., Zhang, G.G. and Taylor, L.S., 2011. Dissolution and precipitation behavior of amorphous solid dispersions. J Pharm Sci. 100: 3316-31.

Basalious, E.B., El-Sebaie, W. and El-Gazayerly, O., 2011. Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a class II BCS drug using polymeric surfactants and crystallization inhibitors: development of controlled-release tablets. AAPS PharmSciTech. 12: 799-810.

Dhawan, S., Kapil, R. and Singh, B., 2011. Formulation development and systematic optimization of solid lipid nanoparticles of quercetin for improved brain delivery. J Pharm Pharmacol. 63: 342-51.

Evans, S.J., Dalton, G.R. and Levi, A.J., 2000. Experimental studies on myocardial stretch and ventricular arrhythmia in hypertrophied and non-hypertrophied hearts. J Cardiovasc Risk. 7: 163-75.

Feng, J., Xu, L., Gao, R., Luo, Y. and Tang, X., 2012. Evaluation of polymer carriers with regard to the bioavailability enhancement of bifendate solid dispersions prepared by hot-melt extrusion. Drug Dev Ind Pharm. 38: 735-43.

Gill, P., Moghadam, T.T. and Ranjbar, B., 2010. Differential scanning calorimetry techniques: applications in biology and nanoscience. J Biomol Tech. 21: 167-93.

Grant, A.O., 2003. Recent advances in the treatment of arrhythmias. Circ J. 67: 651-5.

Higashi, K., Yamamoto, K., Pandey, M.K., Mroue, K.H., Moribe, K. and Ramamoorthy, A., 2014. Insights into atomic-level interaction between mefenamic acid and eudragit EPO in a supersaturated solution by high-resolution magic-angle spinning NMR spectroscopy. Mol Pharm. 11: 351-7.

Jain, S.K., Agrawal, G.P. and Jain, N.K., 2008. Floating microspheres as drug delivery system: newer approaches. Curr Drug Deliv. 5: 220-3.

Kapil, R., Dhawan, S., Beg, S. and Singh, B., 2013. Buccoadhesive films for once-a-day administration of rivastigmine: systematic formulation development and pharmacokinetic evaluation. Drug Dev Ind Pharm. 39: 466-80.

Karavas, E., Georgarakis, E. and Bikiaris, D., 2006. Felodipine nanodispersions as active core for predictable pulsatile chronotherapeutics using PVP/HPMC blends as coating layer. Int J Pharm. 313: 189-97.

Karavas, E., Ktistis, G., Xenakis, A. and Georgarakis, E., 2005. Miscibility behavior and formation mechanism of stabilized felodipine-polyvinylpyrrolidone amorphous solid dispersions. Drug Dev Ind Pharm. 31: 473-89.

Pagar, K.P. and Vavia, P.R., 2012. Felodipine beta-cyclodextrin complex as an active core for time delayed chronotherapeutic treatment of hypertension. Acta Pharm. 62: 395-410.

Pattnaik, S., Swain, K., Mallick, S. and Lin, Z., 2011. Effect of casting solvent on crystallinity of ondansetron in transdermal films. Int J Pharm. 406: 106-10.

Peters, R.W., Brooks, M.M., Zoble, R.G., Liebson, P.R. and Seals, A.A., 1996. Chronobiology of acute myocardial infarction: cardiac arrhythmia suppression trial (CAST) experience. Am J Cardiol. 78: 1198-201.

Raina, S.A., Zhang, G.G., Alonzo, D.E., Wu, J., Zhu, D., Catron, N.D., Gao, Y. and Taylor, L.S., 2014. Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs. J Pharm Sci. 103: 2736-48.

Rezaei Mokarram, A., Kebriaee Zadeh, A., Keshavarz, M., Ahmadi, A. and Mohtat, B., 2010. Preparation and in-vitro evaluation of indomethacin nanoparticles. Daru. 18: 185-92.

Roy, P. and Shahiwala, A., 2009. Multiparticulate formulation approach to pulsatile drug delivery: current perspectives. J Control Release. 134: 74-80.

Sarode, A.L., Malekar, S.A., Cote, C. and Worthen, D.R., 2014a. Hydroxypropyl cellulose stabilizes amorphous solid dispersions of the poorly water soluble drug felodipine. Carbohydr Polym. 112: 512-9.

Sarode, A.L., Wang, P., Obara, S. and Worthen, D.R., 2014b. Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs. Eur J Pharm Biopharm. 86: 351-60.

Schmid, M.B., Hopfner, R.J., Lenhof, S., Hummler, H.D. and Fuchs, H., 2013. Cerebral desaturations in preterm infants: a crossover trial on influence of oxygen saturation target range. Arch Dis Child Fetal Neonatal Ed. 98: F392-8.

Singh, B., Kapil, R., Nandi, M. and Ahuja, N., 2011. Developing oral drug delivery systems using formulation by design: vital precepts, retrospect and prospects. Expert Opin Drug Deliv. 8: 1341-60.

Singh, B., Pahuja, S., Kapil, R. and Ahuja, N., 2009. Formulation development of oral controlled release tablets of hydralazine: optimization of drug release and bioadhesive characteristics. Acta Pharm. 59: 1-13.

Singh, B., Singh, R., Bandyopadhyay, S., Kapil, R. and Garg, B., 2013. Optimized nanoemulsifying systems with enhanced bioavailability of carvedilol. Colloids Surf B Biointerfaces. 101: 465-74.

Takahara, A., Sugiyama, A., Dohmoto, H., Yoshimoto, R. and Hashimoto, K., 2000. Antiarrhythmic and cardiohemodynamic effects of a novel Ca(2+) channel blocker, AH-1058, assessed in canine arrhythmia models. Eur J Pharmacol. 398: 107-12.

Tapas, A.R., Kawtikwar, P.S. and Sakarkar, D.M., 2009. Enhanced dissolution rate of felodipine using spherical agglomeration with Inutec SP1 by quasi emulsion solvent diffusion method. Res Pharm Sci. 4: 77-84.

Tuntikulwattana, S., Mitrevej, A., Kerdcharoen, T., Williams, D.B. and Sinchaipanid, N., 2010. Development and optimization of micro/nanoporous osmotic pump tablets. AAPS PharmSciTech. 11: 924-35.

Yang, M., Xie, S., Li, Q., Wang, Y., Chang, X., Shan, L., Sun, L., Huang, X. and Gao, C., 2014. Effects of polyvinylpyrrolidone both as a binder and pore-former on the release of sparingly water-soluble topiramate from ethylcellulose coated pellets. Int J Pharm. 465: 187-96.

Zhang, X., Wang, Y., Wang, J. and Li, S., 2007. Effect of pore former on the properties of casted film prepared from blends of Eudragit NE 30 D and Eudragit L 30 D-55. Chem Pharm Bull (Tokyo). 55: 1261-3.



  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Indonesian J Pharm indexed by:


analytics View My Stats