Novel Hot Melt Extruded Matrices of Hydroxypropyl Cellulose and Amorphous Felodipine–Plasticized Hydroxypropyl Methylcellulose as Controlled Release Systems


Hydroxypropyl methylcellulose (HPMC) is a hydrophilic retarding-release polymer with the limited application in hot melt extrusion (HME) due to its high glass transition temperature (Tg 181–191°C) and melt viscosity. The aim of this study is to develop hot melt extruded matrices using hydroxypropyl cellulose (HPC) and felodipine (FLDP) with HPMC for controlled release and explore the relations of their specialty, processability, and structure with the product properties. Results showed that FLDP/HPCEF/HPMC can be extruded at 160°C with torques not more than 0.5 N·m. The extruded matrices of FLDP/HPCEF/HPMCK15M (10:45:45 and 30:35:35) achieved the controlled release for 24 h. Rheological behaviors demonstrated that HPCEF and FLDP were miscible with HPMCK15M, attaining maximum 30% FLDP soluble in the molten mixtures. HPCEF and FLDP decreased the complex viscosity and plasticized HPMCK15M to improve the extrusion processing. DSC and FT-IR indicated that the molten soluble FLDP was amorphous in the extruded matrices by hydrogen bonding with HPCEF/HPMCK15M. SEM/energy-dispersive X-ray microanalysis illustrated that the microstructure of extrudates was surface dense and interior loose, and FLDP was homogenously dispersed. Three-point bending test revealed that the plasticizers of HPCEF and FLDP contributed differently to the mechanical properties. HPCEF decreased the flexural modulus of HPMCK15M while that of HPCEF/HPMCK15M was increased by FLDP. Besides controlled release, low moisture absorption and enhanced stability were also the correlated achievements. Therefore, HPCEF-combined poorly water-soluble drugs to plasticize HPMCK15M provide an alternative novel potential approach to realize the controlled-release delivery via HME.

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Active pharmaceutical ingredients


Amorphous solid dispersions


Chinese Pharmacopoeia


Differential scanning calorimetry


Energy-dispersive X-ray microanalysis




Fourier transform infrared spectroscopy


Hot melt extrusion


Hydroxypropyl cellulose


Hydroxypropyl methylcellulose


Phosphate-buffered solution


Polyethylene glycol


Propylene glycol


Physical mixtures


Relative humidity


Sodium dodecyl sulfate


Scanning electron microscopy

T g :

Glass transition temperature

T m :

Melting temperature


United States Pharmacopoeia




  1. 1.

    Van Renterghem J, Kumar A, Vervaet C, Remon JP, Nopens I, Vander Heyden Y, et al. Elucidation and visualization of solid-state transformation and mixing in a pharmaceutical mini hot melt extrusion process using in-line Raman spectroscopy. Int J Pharm 2017;517(1–2):119–127.

    Article  Google Scholar 

  2. 2.

    Feng X, Zhang F. Twin-screw extrusion of sustained-release oral dosage forms and medical implants. Drug Deliv Transl Res. 2018;8(6):1694–713.

    CAS  Article  Google Scholar 

  3. 3.

    Liu X, Ma X, Kun E, Guo X, Yu Z, Zhang F. Influence of lidocaine forms (salt vs. freebase) on properties of drug-eudragit(R) L100-55 extrudates prepared by reactive melt extrusion. Int J Pharm. 2018;547(1–2):291–302.

    CAS  Article  Google Scholar 

  4. 4.

    Zhang F. Physicochemical properties and mechanisms of drug release from melt-extruded granules consisting of chlorpheniramine maleate and Eudragit FS. Drug Dev Ind Pharm. 2015;42(4):563–71.

    PubMed  Google Scholar 

  5. 5.

    Palazi E, Karavas E, Barmpalexis P, Kostoglou M, Nanaki S, Christodoulou E, et al. Melt extrusion process for adjusting drug release of poorly water soluble drug felodipine using different polymer matrices. Eur J Pharm Sci. 2018;114:332–45.

    CAS  Article  Google Scholar 

  6. 6.

    Dierickx L, Saerens L, Almeida A, De Beer T, Remon JP, Vervaet C. Co-extrusion as manufacturing technique for fixed-dose combination mini-matrices. Eur J Pharm Biopharm. 2012;81(3):683–9.

    CAS  Article  Google Scholar 

  7. 7.

    Verstraete G, Mertens P, Grymonpré W, Van Bockstal PJ, De Beer T, Boone MN, et al. A comparative study between melt granulation/compression and hot melt extrusion/injection molding for the manufacturing of oral sustained release thermoplastic polyurethane matrices. Int J Pharm. 2016;513(1–2):602–11.

    CAS  Article  Google Scholar 

  8. 8.

    Zhang F, McGinity JW. Properties of sustained-release tablets prepared by hot-melt extrusion. Pharm Dev Technol. 1999;4(2):241–50.

    CAS  Article  Google Scholar 

  9. 9.

    Cossé A, König C, Lamprecht A, Wagner KG. Hot melt extrusion for sustained protein release: matrix erosion and in vitro release of PLGA-based implants. AAPS PharmSciTech. 2017;18(1):15–26.

    Article  Google Scholar 

  10. 10.

    Notario-Pérez F, Cazorla-Luna R, Martín-Illana A, Ruiz-Caro R, Tamayo A, Rubio J, et al. Optimization of tenofovir release from mucoadhesive vaginal tablets by polymer combination to prevent sexual transmission of HIV. Carbohydr Polym. 2018;179:305–16.

    Article  Google Scholar 

  11. 11.

    Zhang J, Yang W, Vo AQ, Feng X, Ye X, Kim DW, et al. Hydroxypropyl methylcellulose-based controlled release dosage by melt extrusion and 3D printing: structure and drug release correlation. Carbohydr Polym. 2017;177:49–57.

    CAS  Article  Google Scholar 

  12. 12.

    Aho J, Halme A, Boetker J, Water JJ, Bohr A, Sandler N, et al. The effect of HPMC and MC as pore formers on the rheology of the implant microenvironment and the drug release in vitro. Carbohydr Polym. 2017;177:433–42.

    CAS  Article  Google Scholar 

  13. 13.

    Meena A, Parikh T, Gupta SS, Serajuddin ATM. Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion—II: cellulosic polymers. J Excipients Food Chem. 2014;5(1):46–55.

    Google Scholar 

  14. 14.

    Ma D, Djemai A, Gendron CM, Xi H, Smith M, Kogan J, et al. Development of a HPMC-based controlled release formulation with hot melt extrusion (HME). Drug Dev Ind Pharm. 2013;39(7):1070–83.

    CAS  Article  Google Scholar 

  15. 15.

    Sarode AL, Malekar SA, Cote C, Worthen DR. Hydroxypropyl cellulose stabilizes amorphous solid dispersions of the poorly water soluble drug felodipine. Carbohydr Polym. 2014;112:512–9.

    CAS  Article  Google Scholar 

  16. 16.

    Paradkar A, Kelly A, Coates P, York P. Shear and extensional rheology of hydroxypropyl cellulose melt using capillary rheometry. J Pharm Biomed Anal. 2009;49(2):304–10.

    CAS  Article  Google Scholar 

  17. 17.

    Repka MA, Gutta K, Prodduturi S, Munjal M, Stodghill SP. Characterization of cellulosic hot-melt extruded films containing lidocaine. Eur J Pharm Biopharm. 2005;59(1):189–96.

    CAS  Article  Google Scholar 

  18. 18.

    Wilson MR, Jones DS, Andrews GP. The development of sustained release drug delivery platforms using melt-extruded cellulose-based polymer blends. J Pharm Pharmacol. 2017;69(1):32–42.

    CAS  Article  Google Scholar 

  19. 19.

    Chen J, Chen Y, Huang W, Wang H, Du Y, Xiong S. Bottom-up and top-down approaches to explore sodium dodecyl sulfate and Soluplus on the crystallization inhibition and dissolution of felodipine extrudates. J Pharm Sci. 2018;107(9):2366–76.

    CAS  Article  Google Scholar 

  20. 20.

    Ferrero C, Massuelle D, Jeannerat D, Doelker E. Towards elucidation of the drug release mechanism from compressed hydrophilic matrices made of cellulose ethers. III. Critical use of thermodynamic parameters of activation for modeling the water penetration and drug release processes. J Control Release. 2013;170(2):175–82.

    CAS  Article  Google Scholar 

  21. 21.

    Körner A, Piculell L, Iselau F, Wittgren B, Larsson A. Influence of different polymer types on the overall release mechanism in hydrophilic matrix tablets. Molecules. 2009;14(8):2699–716.

    Article  Google Scholar 

  22. 22.

    Jain AK, Söderlind E, Viridén A, Schug B, Abrahamsson B, Knopke C, et al. The influence of hydroxypropyl methylcellulose (HPMC) molecular weight, concentration and effect of food on in vivo erosion behavior of HPMC matrix tablets. J Control Release. 2014;187:50–8.

    CAS  Article  Google Scholar 

  23. 23.

    Chen W, Desai D, Good D, Crison J, Timmins P, Paruchuri S, et al. Mathematical model-based accelerated development of extended-release metformin hydrochloride tablet formulation. AAPS PharmSciTech. 2016;17(4):1007–13.

    CAS  Article  Google Scholar 

  24. 24.

    Aho J, Edinger M, Botker J, Baldursdottir S, Rantanen J. Oscillatory shear rheology in examining the drug-polymer interactions relevant in hot melt extrusion. J Pharm Sci. 2016;105(1):160–7.

    CAS  Article  Google Scholar 

  25. 25.

    Yang M, Wang P, Suwardie H, Gogos C. Determination of acetaminophen’s solubility in poly(ethylene oxide) by rheological, thermal and microscopic methods. Int J Pharm. 2011;403(1–2):83–9.

    CAS  Article  Google Scholar 

  26. 26.

    Tang XC, Pikal MJ, Taylor LS. A spectroscopic investigation of hydrogen bond patterns in crystalline and amorphous phases in dihydropyridine calcium channel blockers. Pharm Res. 2002;19(4):477–83.

    CAS  Article  Google Scholar 

  27. 27.

    Konno H, Taylor LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci. 2006;95(12):2692–705.

    CAS  Article  Google Scholar 

  28. 28.

    Chen Y, Liu C, Chen Z, Su C, Hageman M, Hussain M, et al. Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions. Mol Pharm. 2015;12(2):576–89.

    CAS  Article  Google Scholar 

  29. 29.

    Xie T, Taylor LS. Effect of temperature and moisture on the physical stability of binary and ternary amorphous solid dispersions of celecoxib. J Pharm Sci. 2017;106(1):100–10.

    CAS  Article  Google Scholar 

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We greatly appreciate the Thermo Fisher Scientific for providing the support of rheological study.


This work was supported by the National Natural Science Foundation of China (No. 30701059) and the Natural Science Foundation of Zhejiang Province (No. LY13H300004).

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Correspondence to Subin Xiong.

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Yi, S., Wang, J., Lu, Y. et al. Novel Hot Melt Extruded Matrices of Hydroxypropyl Cellulose and Amorphous Felodipine–Plasticized Hydroxypropyl Methylcellulose as Controlled Release Systems. AAPS PharmSciTech 20, 219 (2019).

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  • cellulose
  • felodipine
  • plasticization
  • controlled release
  • hot melt extrusion