Drug Delivery and Translational Research

, Volume 8, Issue 6, pp 1679–1693 | Cite as

Extended release delivery system of metoprolol succinate using hot-melt extrusion: effect of release modifier on methacrylic acid copolymer

  • Kiran P. Sawant
  • Ritesh Fule
  • Mohammed Maniruzzaman
  • Purnima D. Amin
Original Article


The current study reports on the manufacturing of extended release dosage forms of metoprolol succinate via hot-melt extrusion (HME) technology. Either Eudragit®S100 and Eudragit®L100 alone or in combination with release modifying agent Polyox™ WSR 303 and Eudragit®L100-55 were processed to obtain complete and faster release. Metoprolol succinate with similar solubility parameters to polymer was dispersed in polymer matrix and was characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Stability of drug after extrusion was confirmed by thermogravimetric analysis and high-performance liquid chromatography. Physical characterization method exhibited that the drug was homogeneously dispersed in non-crystalline state in Eudragit®L100-55-based formulations whereas in semi-crystalline state in Polyox™ WSR 303. The drug release percentage was below 3 and 40% in 0.1 N HCL with Eudragit®L100-55- and Polyox™ WSR 303-containing formulations, respectively, and exhibited pH-dependent dissolution properties. The drug-release mechanism was anomalous with Polyox™ WSR 303 formulations whereas diffusion through pore formation was obtained with Eudragit®L100-55. Both Eudragit®L100-55 and Polyox™ WSR 303 changed the release mechanism and kinetics of drug release from thermally processed dosage forms. The optimized stable formulation is similar to the marketed formulation with F2 value of 72.36. Thus, it can be concluded that HME was exploited as an effective process for the preparation of controlled release matrix system based on pH-dependent polymer matrices Eudragit®S100 and Eudragit®L100.


Hot-melt extrusion Metoprolol succinate Eudragit®S100 Eudragit®L100 Eudragit®L100-55 Polyox™ WSR 303 Extended release Release-modifying agent 



Hot-melt extrusion


Metoprolol succinate






Polyox™ WSR 303





The author is thankful to UGC (SAP) for providing the research fellowship and Institute of Chemical Technology, ELITE status (Mumbai, India) for providing all facilities and guidance.

Compliance with ethical standards


The authors declare that they have no conflict of interest.


  1. 1.
    Repka MA, Thumma S, Upadhye SB, Battu SK, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm. 2007;33:909–26.CrossRefPubMedGoogle Scholar
  2. 2.
    Vynckier AK, Dierickx L, Saerens L, Voorspoels J, Gonnissen Y, De Beer T, et al. Hot-melt co-extrusion for the production of fixed-dose combination products with a controlled release ethylcellulose matrix core. Int J Pharm. 2014;464(1–2):65–74.CrossRefPubMedGoogle Scholar
  3. 3.
    Almeida A, Possemiers S, Boone MN, De Beer T, Quinten T, Hoorebeke VL, et al. Ethylene vinyl acetate as matrix for oral sustained release dosage forms produced via hot-melt extrusion. Eur J Pharm Biopharm. 2011;77(2):297–305.CrossRefPubMedGoogle Scholar
  4. 4.
    Loreti G, Maroni A, Del Curto MD, Melocchi A, Gazzaniga A, Zema L, et al. Evaluation of hot-melt extrusion technique in the preparation of HPC matrices for prolonged release. Eur J Pharm Sci. 2014;52:77–85.CrossRefPubMedGoogle Scholar
  5. 5.
    Ozguney I, Shuwisitkul D, Bodmeier R, et al. Development and characterization of extended release Kollidon® SR mini-matrices prepared by hot-melt extrusion. Eur J Pharm Biopharm. 2009;73(1):140–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, et al. Pharmaceutical applications of hot-melt extrusion: part II. Drug Dev Ind Pharm. 2007;33(10):1043–57.CrossRefPubMedGoogle Scholar
  7. 7.
    Repka MA, Majumdar S, Battu SK, Srirangam R, Upadhye SB, et al. Applications of hot-melt extrusion for drug delivery. Expert Opin Drug Deliv. 2008;5(12):1357–76.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Verhoeven E, De Beer TRM, Van den Mooter G, Remon JP, Vervaet C, et al. Influence of formulation and process parameters on the release characteristics of ethylcellulose sustained-release mini-matrices produced by hot-melt extrusion. Eur J Pharm Biopharm. 2008;69(1):312–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Vynckier AK, Dierickx L, Saerens L, Voorspoels J, Gonnissen Y, De Beer T, et al. Hot-melt co-extrusion for the production of fixed-dose combination products with a controlled release ethyl cellulose matrix core. Int J Pharm. 2014;464(1–2):65–74.CrossRefPubMedGoogle Scholar
  10. 10.
    Eirin ER, Rodriguez BS, Amoza JLG, Pacheco RM, et al. Evaluation of the hyperbranched polymer Hybrane H1500 for production of matricial controlled-release particles by hot-melt extrusion. Int J Pharm. 2014;461(1–2):469–77.CrossRefGoogle Scholar
  11. 11.
    Zhang F, McGinity JW, et al. Properties of sustained release tablets prepared by hot-melt extrusion. Pharm Dev Technol. 1999;4(2):241–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Christopher RY, Caroline D, Matteo C, Thomas F, Kurt AF, Ali Rajabi S, et al. Physicochemical characterization and mechanisms of release of theophylline from melt-extruded dosage forms based on a methacrylic acid copolymer. Int J Pharm. 2005;301(1–2):112–20.Google Scholar
  13. 13.
    Raimar L, Seung KJ, Gordon LA, et al. Pharmacokinetics of an immediate release a controlled release and a two pulse dosage form in dogs. Eur J Pharm Biopharm. 2000;60:17–23.Google Scholar
  14. 14.
    Jobin G, Cortot A, Godbillon J, Duval M, Schoeller JP, Hirtz J, et al. Investigation of drug absorption from the gastrointestinal tract of man. I. Metoprolol in the stomach, duodenum and jejunum. Br J Clin Pharmacol. 1985;19:97S–105S.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Godbillon J, Evard D, Vidon N, Duval M, Schoeller JP, Bernier JJ, et al. Investigation of drug absorption from the gastrointestinal tract of man. III. Metoprolol in the colon. Br J Clin Pharmacol. 1985;19:113S–8S.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Vidon N, Evard D, Godbillon J, Rongier M, Duval M, Schoeller JP, et al. Investigation of drug absorption from the gastrointestinal tract of man:II. Metoprolol in jejenum and ileum. Br J Clin Pharmacol. 1985;19:107–12.CrossRefGoogle Scholar
  17. 17.
    Hoftyzer PJ, Krevelen DWV. Properties of polymers. Amsterdam: Elsevier; 1976.Google Scholar
  18. 18.
    Foster A, Hempenstall J, Tucker I, Rades T. Selection of excipients formelt extrusion with two poorlywater-soluble drugs by solubility parameter calculationand thermal analysis. Int J Pharm. 2001;226(1–2):147–61.CrossRefGoogle Scholar
  19. 19.
    Sarode AL, Sandhu H, Shah N, Malick W, Zia H. Hot melt extrusion (HME) for amorphous solid dispersions: predictive tools for processing and impact of drug–polymer interactions on supersaturation. Eur J Pharm Sci. 2013;48:371–84.CrossRefPubMedGoogle Scholar
  20. 20.
    Crowley MM, Schroeder AB, Kucera S, SuneelaProdduturi MAR, McGinity JW. The influence of guaifenesin and ketoprofen on the properties of hot-melt extruded polyethylene oxide films. Eur J Pharm Sci. 2004;22:409–18.CrossRefPubMedGoogle Scholar
  21. 21.
    Teja K, Aleksandra D, Odon P, Rok S, Stanko S. Determination of solubility parameters of ibuprofen and ibuprofen lysinate. Molecules. 2015;20:21549–68.CrossRefGoogle Scholar
  22. 22.
    Kalisetty S. Ultra performance liquid chromatographic method development and validation for the quantification of impurities and degradation products in the metoprolol succinate ER tablets. Int J Pharm Bio Sci. 2012;2(4):247–55.Google Scholar
  23. 23.
    Patel VM, et al. Mucoadhesive bilayer tablets of propranolol hydrochloride, AAPS. Pharm. SciTech. 2007;8(3):77.Google Scholar
  24. 24.
    Malviya R. Swelling and erosion based formulations for the treatment of chronic seizures using (3)2Factorial design. Middle-East J Sci Res. 2012;11(1):77–84.Google Scholar
  25. 25.
    Carelli V, Colo GD, Nannipieri E, Poli B, Serafini MS, et al. Polyoxyethylene-poly(methacrylic acid-co-methyl methacrylate) compounds for site-specific peroral delivery. Int J Pharm. 2000;202:103–12.CrossRefPubMedGoogle Scholar
  26. 26.
    Colo GD, Burgalassi S, Chetoni P, Fiaschi MP, Zambito Y, Saettone MF, et al. Gel-forming erodible inserts for ocular controlled delivery ofofloxacin. Int J Pharm. 2001;215:101–11.CrossRefPubMedGoogle Scholar
  27. 27.
    Colo GD, Falchi S, Zambito Y, et al. In vitro evaluation of a system for pH-controlled peroraldelivery of metformin. J Control Release. 2002;80:119–28.CrossRefPubMedGoogle Scholar
  28. 28.
    Gallardo D, Skalsky B, Kleinebudde P, et al. Controlled release solid dosage forms using combinations. Pharm Dev Technol. 2008;13:413–23.CrossRefPubMedGoogle Scholar
  29. 29.
    Mehta KA, Kislalioglu MS, Phuapradit W, Malick AW, Shah NH, et al. Release performance of a poorly soluble drug from a novel, Eudragit®-based multi-unit erosion matrix. Int J Pharm. 2001;213:7–12.CrossRefPubMedGoogle Scholar
  30. 30.
    Ceballos A, Cirri M, Maestrelli F, Corti G, Mura P, et al. Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets. Farmaco. 2005;60:913–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Quinten T, Andrews GP, de Beer T, Saerens L, Bouquet W, Jones DS, et al. Preparation and evaluation of sustained release matrix tablets based on metoprolol and an acrylic carrier using injection molding. AAPS PharmSciTech. 2012;13(4):1197–211.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Parikh T, Gupta Simerdeep S, Meena A, Serajuddin Abu TM. Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion—III. Polymethacrylates and polymethacrylic acid based polymers. J Excipients Food Chem. 2014;5(1):56–64.Google Scholar
  33. 33.
    Foster A, Hempenstall J, Tucker I, Rades T. Selection of excipients formelt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis. Int J Pharm. 2001;226(1–2):147–61.CrossRefGoogle Scholar
  34. 34.
    Benetti C, Colombo P, Wong TW, et al. Cellulose, ethylene oxide, and acrylic based polymers in assembled module technology (dome matrix). Handbook of polymers for pharmaceutical technologies, biodegradable. Polymer. 2015;3:236.Google Scholar
  35. 35.
    Verhoeven E, De Beer TR, Schacht E, Van den Mooter G, Remon JP, Vervaet C. Influence of polyethylene glycol/polyethylene oxide on the release characteristics of sustained-release ethyl cellulose mini-matrices produced by hot-melt extrusion: in vitro and in vivo evaluations. Eur J Pharm Biopharm. 2009;72(2):463–70.CrossRefPubMedGoogle Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  • Kiran P. Sawant
    • 1
  • Ritesh Fule
    • 1
    • 2
  • Mohammed Maniruzzaman
    • 3
  • Purnima D. Amin
    • 1
  1. 1.Department of Pharmaceutical Sciences and TechnologyInstitute of Chemical TechnologyMumbaiIndia
  2. 2.Faculty of Pharmaceutics DepartmentH.K. College of PharmacyMumbaiIndia
  3. 3.Department of Pharmacy (Chemistry), School of Life SciencesUniversity of SussexFalmer-BrightonUK

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