Skip to main content
SpringerLink
Log in

Melt Extrusion for a High Melting Point Compound with Improved Solubility and Sustained Release

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The objective of the current study was to develop an amorphous solid dispersion for a high melting point compound, griseofulvin (GRF), with an enhanced solubility and a controlled release pattern utilizing hot melt extrusion (HME) technology. Hypromellose acetate succinate (HPMCAS, Shin-Etsu AQOAT®, medium particle size) was explored as the polymeric carrier, while hypromellose (HPMC, Metolose® SR) was chosen as the release rate control agent. GRF presented an HPMCAS grade-dependent solubility: AS-HMP > AS-MMP > AS-LMP. At 10 wt.% loading, the release of GRF was prolonged to 6 h with the incorporation of 10% HPMC 90SH-100SR, while its solubility was enhanced up to sevenfold. Fourier transform infrared spectroscopy (FT-IR) identified the H-bonding between drug and polymers. Element analysis utilizing X-ray photoelectron spectroscopy (XPS) discovered that less GRF aggregated on the surface of binary powders compared with ternary powders containing HPMC, indicating the relatively poor wettability of the latter one. The morphology of extrudates was observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM), illustrating a much smoother and uniform surface of binary extrudates. Immediate release tablets including 10% super-disintegrant L-HPC were able to achieve identical dissolution profile as the powders of extrudates.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Shah S, Maddineni S, Lu J, Repka MA. Melt extrusion with poorly soluble drugs. Int J Pharm. 2013;453(1):233–52. doi:10.1016/j.ijpharm.2012.11.001.

    Article  CAS  PubMed  Google Scholar 

  2. Lu J, Cuellar K, Hammer NI, Jo S, Gryczke A, Kolter K, et al. Solid-state characterization of Felodipine-Soluplus amorphous solid dispersions. Drug Dev Ind Pharm. 2016;42(3):485–96. doi:10.3109/03639045.2015.1104347.

    Article  CAS  PubMed  Google Scholar 

  3. Sowa M, Ślepokura K, Matczak-Jon E. Improving solubility of fisetin by cocrystallization. CrystEngComm. 2014;46:10592–601.

    Article  Google Scholar 

  4. Serajuddin AT. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59(7):603–16. doi:10.1016/j.addr.2007.05.010.

    Article  CAS  PubMed  Google Scholar 

  5. Keen JM, Hughey JR, Bennett RC, Jannin V, Rosiaux Y, Marchaud D, et al. Effect of tablet structure on controlled release from supersaturating solid dispersions containing glyceryl behenate. Mol Pharm. 2015;12(1):120–6. doi:10.1021/mp500480y.

    Article  CAS  PubMed  Google Scholar 

  6. Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–72. doi:10.1002/jps.21650.

    Article  CAS  PubMed  Google Scholar 

  7. Rodriguez-Hornedo N, Murphy D. Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems. J Pharm Sci. 1999;88(7):651–60. doi:10.1021/js980490h.

    Article  CAS  PubMed  Google Scholar 

  8. Tran PH, Tran TT, Park JB, Lee BJ. Controlled release systems containing solid dispersions: strategies and mechanisms. Pharm Res. 2011;28(10):2353–78. doi:10.1007/s11095-011-0449-y.

    Article  CAS  PubMed  Google Scholar 

  9. Brown C, DiNunzio J, Eglesia M, Forster S, Lamm M, Lowinger M, et al. Hot-melt extrusion for solid dispersions: composition and design considerations. In: Shah N, Sandhu H, Choi DS, Chokshi H, Malick AW, editors. Amorphous solid dispersions: theory and practice. New York, Heidelberg, Dordrecht, London: Springer; 2014.

    Google Scholar 

  10. Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19(12):930–4.

    Article  Google Scholar 

  11. Lu J, Obara S, Ioannidis N, Suwardie J, Gogos C, Kikuchi S. Understanding the processing window of hypromellose acetate succinate for hot-melt extrusion, part I: polymer characterization and hot-melt extrusion. Adv Polym Technol 2016. doi: 00, 21652, 10.1002/adv.21652.

  12. Hughey JR, Keen JM, Brough C, Saeger S, McGinity JW. Thermal processing of a poorly water-soluble drug substance exhibiting a high melting point: the utility of KinetiSol® dispersing. Int J Pharm. 2011;419(1–2):222–30. doi:10.1016/j.ijpharm.2011.08.007.

    Article  CAS  PubMed  Google Scholar 

  13. Sarode AL, Obara S, Tanno FK, Sandhu H, Iyer R, Shah N. Stability assessment of hypromellose acetate succinate (HPMCAS) NF for application in hot melt extrusion (HME). Carbohydr Polym. 2014;101:146–53. doi:10.1016/j.carbpol.2013.09.017.

    Article  CAS  PubMed  Google Scholar 

  14. Karandikar H, Ambardekar R, Kelly A, Gough T, Paradkar A. Systematic identification of thermal degradation products of HPMCP during hot melt extrusion process. Int J Pharm. 2015;486(1–2):252–8. doi:10.1016/j.ijpharm.2015.04.007.

    Article  CAS  PubMed  Google Scholar 

  15. Crowley MM, Zhang F, Koleng JJ, McGinity JW. Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion. Biomaterials. 2002;23(21):4241–8.

    Article  CAS  PubMed  Google Scholar 

  16. Al-Obaidi H, Brocchini S, Buckton G. Anomalous properties of spray dried solid dispersions. J Pharm Sci. 2009;98(12):4724–37. doi:10.1002/jps.21782.

    Article  CAS  PubMed  Google Scholar 

  17. Shah N, Iyer RM, Mair HJ, Choi DS, Tian H, Diodone R, et al. Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process. J Pharm Sci. 2013;102(3):967–81. doi:10.1002/jps.23425.

    Article  CAS  PubMed  Google Scholar 

  18. DiNunzio JC, Brough C, Miller DA, Williams RO 3rd, McGinity JW. Fusion processing of itraconazole solid dispersions by kinetisol dispersing: a comparative study to hot melt extrusion. J Pharm Sci. 2010;99(3):1239–53.

    Article  CAS  PubMed  Google Scholar 

  19. Lakshman JP, Cao Y, Kowalski J, Serajuddin AT. Application of melt extrusion in the development of a physically and chemically stable high-energy amorphous solid dispersion of a poorly water-soluble drug. Mol Pharm. 2008;5(6):994–1002. doi:10.1021/mp8001073.

    Article  CAS  PubMed  Google Scholar 

  20. Verreck G, Decorte A, Li H, Tomasko D, Arien A, Peeters J, et al. The effect of pressurized carbon dioxide as a plasticizer and foaming agent on the hot melt extrusion process and extrudate properties of pharmaceutical polymers. J Supercrit Fluids. 2006;38(3):383–91.

    Article  CAS  Google Scholar 

  21. Yalkowsky SH, Dannenfelser RM. Aquasol database of aqueous solubility. College of Pharmacy, University of Arizona, Tucson, AZ. 1992.

  22. Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17(4):397–404.

    Article  CAS  PubMed  Google Scholar 

  23. Chiou WL, Riegelman S. Preparation and dissolution characteristics of several fast-release solid dispersions of griseofulvin. J Pharm Sci. 1969;58:1505–10.

    Article  CAS  PubMed  Google Scholar 

  24. Roine J, Kaasalainen M, Peurla M, Correia A, Araujo F, Santos HA, et al. Controlled dissolution of griseofulvin solid dispersions from electrosprayed enteric polymer micromatrix particles: physicochemical characterization and in vitro evaluation. Mol Pharm. 2015;12(7):2254–64. doi:10.1021/mp500787b.

    Article  CAS  PubMed  Google Scholar 

  25. Saito M, Ugajin T, Nozawa Y, Sadzuka Y, Miyagishima A, Sonobe T. Preparation and dissolution characteristics of griseofulvin solid dispersions with saccharides. Int J Pharm. 2002;249(1–2):71–9.

    Article  CAS  PubMed  Google Scholar 

  26. Bennett RC, Keen JM, Bi Y, Porter S, Dürig T, McGinity JW. Investigation of the interactions of enteric and hydrophilic polymers to enhance dissolution of griseofulvin following hot melt extrusion processing. J Pharm Pharmacol. 2015;67(7):918–38.

    Article  CAS  PubMed  Google Scholar 

  27. 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. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical. Sciences. 2013;48(3):371–84. doi:10.1016/j.ejps.2012.12.012.

    CAS  Google Scholar 

  28. Chen M, Lu J, Deng W, Singh A, Mohammed NN, Repka MA, et al. Influence of processing parameters and formulation factors on the bioadhesive, temperature stability and drug release properties of hot-melt extruded films containing miconazole. AAPS PharmSciTech. 2014;15(3):522–9. doi:10.1208/s12249-013-0029-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Park JB, Lim J, Kang CY, Lee BJ. Drug release-modulating mechanism of hydrophilic hydroxypropylmethylcellulose matrix tablets: distribution of atoms and carrier and texture analysis. Curr Drug Deliv. 2013;10(6):732–41.

    Article  CAS  PubMed  Google Scholar 

  30. Juluri A, Popescu C, Zhou L, Murthy RN, Gowda VK, P CK, et al. Taste masking of griseofulvin and caffeine anhydrous using Kleptose Linecaps DE17 by hot melt extrusion. AAPS PharmSciTech. 2016;17(1):99–105. doi:10.1208/s12249-015-0374-1.

    Article  CAS  PubMed  Google Scholar 

  31. Fell JT, Newton JM. The tensile strength of lactose tablets. J Pharm Pharmacol. 1968;20(8):657–9.

    Article  CAS  PubMed  Google Scholar 

  32. Mitra A, Li L, Marsac P, Marks B, Liu Z, Brown C. Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug. Int J Pharm. 2016;505(1–2):107–14. doi:10.1016/j.ijpharm.2016.03.036.

    Article  CAS  PubMed  Google Scholar 

  33. Ilevbare GA, Liu H, Edgar KJ, Taylor L. Understanding polymer properties important for crystal growth inhibition-impact of chemically diverse polymers on solution crystal growth of ritonavir. Cryst Growth Des. 2012;12(6):3133–43.

    Article  CAS  Google Scholar 

  34. Ueda K, Higashi K, Yamamoto K, Moribe K. The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement. Int J Pharm. 2014;464(1–2):205–13. doi:10.1016/j.ijpharm.2014.01.005.

    Article  CAS  PubMed  Google Scholar 

  35. Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JA. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008;5(6):1003–19. doi:10.1021/mp8000793.

    Article  CAS  PubMed  Google Scholar 

  36. Morott JT, Pimparade M, Park JB, Worley CP, Majumdar S, Lian Z, et al. The effects of screw configuration and polymeric carriers on hot-melt extruded taste-masked formulations incorporated into orally disintegrating tablets. J Pharm Sci. 2015;104(1):124–34. doi:10.1002/jps.24262.

    Article  CAS  PubMed  Google Scholar 

  37. Feng X, Vo A, Patil H, Tiwari RV, Alshetaili AS, Pimparade MB, et al. The effects of polymer carrier, hot melt extrusion process and downstream processing parameters on the moisture sorption properties of amorphous solid dispersions. J Pharm Pharmacol. 2016;68(5):692–704. doi:10.1111/jphp.12488.

    Article  CAS  PubMed  Google Scholar 

  38. Lu J, Shah S, Jo S, Majumdar S, Gryczke A, Kolter K, et al. Investigation of phase diagrams and physical stability of drug-polymer solid dispersions. Pharm Dev Technol. 2015;20(1):105–17. doi:10.3109/10837450.2014.949269.

    Article  CAS  PubMed  Google Scholar 

  39. Schilling SU, Shah NH, Malick AW, Infeld MH, McGinity JW. Citric acid as a solid-state plasticizer for Eudragit RS PO. J Pharm Pharmacol. 2007;59(11):1493–500. doi:10.1211/jpp.59.11.0005.

    Article  PubMed  Google Scholar 

  40. Schilling SU, Lirola HL, Shah NH, Waseem Malick A, McGinity JW. Influence of plasticizer type and level on the properties of Eudragit S100 matrix pellets prepared by hot-melt extrusion. J Microencapsul. 2010;27(6):521–32. doi:10.3109/02652048.2010.484105.

    Article  CAS  PubMed  Google Scholar 

  41. Ghebremeskel AN, Vemavarapu C, Lodaya M. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: selection of polymer-surfactant combinations using solubility parameters and testing the processability. Int J Pharm. 2007;328(2):119–29. doi:10.1016/j.ijpharm.2006.08.010.

    Article  CAS  PubMed  Google Scholar 

  42. 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. doi:10.3109/03639045.2012.702350.

    Article  CAS  PubMed  Google Scholar 

  43. Kunze C, Freier T, Kramer S, Schmitz KP. Anti-inflammatory prodrugs as plasticizers for biodegradable implant materials based on poly(3-hydroxybutyrate). J Mater Sci Mater Med. 2002;13(11):1051–5.

    Article  CAS  PubMed  Google Scholar 

  44. Schram CJ, Beaudoin SP, Taylor LS. Impact of polymer conformation on the crystal growth inhibition of a poorly water-soluble drug in aqueous solution. Langmuir. 2015;31(1):171–9. doi:10.1021/la503644m.

    Article  CAS  PubMed  Google Scholar 

  45. Marks JA, Wegiel LA, Taylor LS, Edgar KJ. Pairwise polymer blends for oral drug delivery. J Pharm Sci. 2014;103(9):2871–83. doi:10.1002/jps.23991.

    Article  CAS  PubMed  Google Scholar 

  46. Craig DQ. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm. 2002;231(2):131–44.

    Article  CAS  PubMed  Google Scholar 

  47. Ohara T, Kitamura S, Kitagawa T, Terada K. Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose. Int J Pharm. 2005;302(1–2):95–102. doi:10.1016/j.ijpharm.2005.06.019.

    Article  CAS  PubMed  Google Scholar 

  48. Tanaka N, Imai K, Okimoto K, Ueda S, Tokunaga Y, Ibuki R, et al. Development of novel sustained-release system, disintegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine (II): in vivo evaluation. Journal of controlled release : official journal of the controlled release. Society. 2006;112(1):51–6. doi:10.1016/j.jconrel.2006.01.020.

    CAS  Google Scholar 

  49. Gao P, Skoug JW, Nixon PR, Ju TR, Stemm NL, Sung KC. Swelling of hydroxypropyl methylcellulose matrix tablets. 2. Mechanistic study of the influence of formulation variables on matrix performance and drug release. J Pharm Sci. 1996;85(7):732–40. doi:10.1021/js9504595.

    Article  CAS  PubMed  Google Scholar 

  50. Crowley MM, Schroeder B, Fredersdorf A, Obara S, Talarico M, Kucera S, et al. Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion. Int J Pharm. 2004;269(2):509–22.

    Article  CAS  PubMed  Google Scholar 

  51. Venkatesh GM, Barnett ME, Owusu-Fordjour C, Galop M. Detection of low levels of the amorphous phase in crystalline pharmaceutical materials by thermally stimulated current spectrometry. Pharm Res. 2001;18(1):98–103.

    Article  CAS  PubMed  Google Scholar 

  52. Zhao Y, Truhlar DG. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Accounts. 2008;120(1):215–41.

    Article  CAS  Google Scholar 

  53. Dahlberg C, Millqvist-Fureby A, Schuleit M. Surface composition and contact angle relationships for differently prepared solid dispersions. Eur J Pharm Biopharm. 2008;70(2):478–85. doi:10.1016/j.ejpb.2008.05.026.

    Article  CAS  PubMed  Google Scholar 

  54. Prasad D, Chauhan H, Atef E. Role of molecular interactions for synergistic precipitation inhibition of poorly soluble drug in supersaturated drug-polymer-polymer ternary solution. Mol Pharm. 2016;13(3):756–65. doi:10.1021/acs.molpharmaceut.5b00655.

    Article  CAS  PubMed  Google Scholar 

  55. Wegiel LA, Mauer LJ, Edgar KJ, Taylor LS. Crystallization of amorphous solid dispersions of resveratrol during preparation and storage: impact of different polymers. J Pharm Sci. 2013;102(1):171–84. doi:10.1002/jps.23358.

    Article  CAS  PubMed  Google Scholar 

  56. Iyer R, Hegde S, Zhang YE, Dinunzio J, Singhal D, Malick A, et al. The impact of hot melt extrusion and spray drying on mechanical properties and tableting indices of materials used in pharmaceutical development. J Pharm Sci. 2013;102(10):3604–13. doi:10.1002/jps.23661.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmaceutical Application Laboratory, Shin-Etsu Chemical Co. Ltd., 140 Commerce Way, Totowa, NJ, 07512, USA

    Jiannan Lu & Sakae Obara

  2. Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, 35205, USA

    Fei Liu

  3. John A. Reif, Jr. Department of Civil and Environmental Engineering, New Jersey Institute of Technology, Newark, NJ, 07102, USA

    Wanyi Fu & Wen Zhang

  4. Cellulose Technical Support Center, Shin-Etsu Chemical Co. Ltd., Yokohama, Kanagawa, 240-0005, Japan

    Shingo Kikuchi

Authors
  1. Jiannan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sakae Obara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wanyi Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shingo Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiannan Lu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, J., Obara, S., Liu, F. et al. Melt Extrusion for a High Melting Point Compound with Improved Solubility and Sustained Release. AAPS PharmSciTech 19, 358–370 (2018). https://doi.org/10.1208/s12249-017-0846-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-017-0846-6

KEY WORDS

Search

Navigation