Skip to main content
SpringerLink
Log in

Development and Characterisation of Modified Release Hard Gelatin Capsules, Based on In Situ Lipid Matrix Formation

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

Abstract

A new technology was developed to form extended release hard gelatin capsules, based on the lipid matrix formation of Gelucire 50/13 and cetostearyl alcohol. Matrices were formed in situ by filling pulverised lipids, ethylcellulose and active ingredients such as diclofenac sodium, acetaminophen and metronidazol into capsules and heating at 63°C for 11 min. Effects of heating were investigated also on the brittleness of capsule shells. Inhibition of the evaporation of water reduced capsule damage. Dissolution tests and texture analysis were performed to discover the release and mechanical profiles of the matrices. Tests were repeated after 1 month storage and results were compared. Gelucire 50/13 alone prolonged drug release but cetostearyl alcohol slowed drug liberation even further. Drug release from all compositions was found to follow first-order kinetic. Significant softening of the matrices was detected during storage in composition containing only Gelucire 50/13, ethylcellulose and diclofenac sodium. Thermal analysis and IR tests were also performed to discover physicochemical interactions between active pharmaceutical ingredients and excipients. Thermal analysis confirmed a notable interaction between diclofenac sodium and Gelucire 50/13 which could be the cause of the observed softening. In conclusion, modified release hard gelatin capsules were developed by a simple and fast monolithic lipid matrix formation method.

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

Similar content being viewed by others

References

  1. Duconseille A, Astruc T, Quintana N, Meersman F, Sante-Lhoutellier V. Gelatin structure and composition linked to hard capsule dissolution: a review. Food Hydrocolloid. 2015;43:360–76. https://doi.org/10.1016/j.foodhyd.2014.06.006.

    Article  CAS  Google Scholar 

  2. Stegemann S, Capsugel B. Hard gelatin capsules today - and tomorrow, 2nd edn. Capsugel Library, BAS 192 E 2002;1–23.

  3. Niederquell A, Kuentz M. Introduction of a theoretical splashing degree to assess the performance of low-viscosity oils in filling of capsules. AAPS PharmSciTech. 2011;12(1):323–30. https://doi.org/10.1208/s12249-011-9589-y.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sultana M, Butt MA, Saeed T, Mahmood R, Ul Hassan S, Hussain K, et al. Effect of rheology and poloxamers properties on release of drugs from silicon dioxide gel-filled hard gelatin capsules-a further enhancement of viability of liquid semisolid matrix technology. AAPS PharmSciTech. 2017;18(6):1998–2010. https://doi.org/10.1208/s12249-016-0674-0.

    Article  CAS  PubMed  Google Scholar 

  5. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88(10):1058–66. https://doi.org/10.1021/Js980403l.

    Article  CAS  PubMed  Google Scholar 

  6. Pissinati R, Oliveira WP. Enteric coating of soft gelatin capsules by spouted bed: effect of operating conditions on coating efficiency and on product quality. Eur J Pharm Biopharm. 2003;55(3):313–21. https://doi.org/10.1016/S0939-6411(03)00002-X.

    Article  CAS  PubMed  Google Scholar 

  7. Gullapalli RP. Soft gelatin capsules (Softgels). J Pharm Sci. 2010;99(10):4107–48. https://doi.org/10.1002/jps.22151.

    Article  CAS  PubMed  Google Scholar 

  8. Semjonov K, Kogermann K, Laidmae I, Antikainen O, Strachan CJ, Ehlers H, et al. The formation and physical stability of two-phase solid dispersion systems of indomethacin in supercooled molten mixtures with different matrix formers. Eur J Pharm Sci. 2017;97:237–46. https://doi.org/10.1016/j.ejps.2016.11.019.

    Article  CAS  PubMed  Google Scholar 

  9. Rosiaux Y, Jannin V, Hughes S, Marchaud D. Solid lipid excipients—matrix agents for sustained drug delivery. J Control Release. 2014;188:18–30. https://doi.org/10.1016/j.jconrel.2014.06.004.

    Article  CAS  PubMed  Google Scholar 

  10. Karanth H, Shenoy VS, Murthy RR. Industrially feasible alternative approaches in the manufacture of solid dispersions: a technical report. AAPS PharmSciTech. 2006;7:E31. https://doi.org/10.1208/pt070487.

    Article  PubMed Central  Google Scholar 

  11. Llinas A, Burley JC, Box KJ, Glen RC, Goodman JM. Diclofenac solubility: independent determination of the intrinsic solubility of three crystal forms. J Med Chem. 2007;50(5):979–83. https://doi.org/10.1021/jm0612970.

    Article  CAS  PubMed  Google Scholar 

  12. Yalkowsky SH, He Y, Jain P. Handbook of aqueous solubility data. 2nd ed. Boca Raton: CRC Press; 2010.

    Book  Google Scholar 

  13. Siepmann F, Muschert S, Flament MP, Leterme P, Gayot A, Siepmann J. Controlled drug release from Gelucire-based matrix pellets: experiment and theory. Int J Pharm. 2006;317(2):136–43. https://doi.org/10.1016/j.ijpharm.2006.03.006.

    Article  CAS  PubMed  Google Scholar 

  14. Eloy JD, Saraiva J, de Albuquerque S, Marchetti JM. Solid dispersion of Ursolic acid in Gelucire 50/13: a strategy to enhance drug release and Trypanocidal activity. AAPS PharmSciTech. 2012;13(4):1436–45. https://doi.org/10.1208/s12249-012-9868-2.

    Article  CAS  Google Scholar 

  15. Guimaraes TF, Comelli ACC, Tacon LA, Cunha TA, Marreto RN, Freitas LAP. Fluidized bed hot melt granulation with hydrophilic materials improves Enalapril maleate stability. AAPS PharmSciTech. 2017;18(4):1302–10. https://doi.org/10.1208/s12249-016-0593-0.

    Article  CAS  PubMed  Google Scholar 

  16. He Y, Johnson JLH, Yalkowsky SH. Oral formulation of a novel antiviral agent, PG301029, in a mixture of gelucire 44/14 and DMA (2: 1, wt/wt). AAPS PharmSciTech. 2005;6:E1. https://doi.org/10.1208/pt060101.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kozlov PV, Burdygina GI. The structure and properties of solid gelatin and the principles of their modification. Polymer. 1983;24(6):651–66. https://doi.org/10.1016/0032-3861(83)90001-0.

    Article  CAS  Google Scholar 

  18. Ku MS, Li WY, Dulin W, Donahue F, Cade D, Benameur H, et al. Performance qualification of a new hypromellose capsule: part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps plus (R), Quali-V (R) and gelatin capsules. Int J Pharm. 2010;386(1–2):30–41. https://doi.org/10.1016/j.ijpharm.2009.10.050.

    Article  CAS  Google Scholar 

  19. Hawley AR, Rowley G, Lough WJ, Chatham S. Physical and chemical characterization of thermosoftened bases for molten filled hard gelatin capsule formulations. Drug Dev Ind Pharm. 1992;18(16):1719–39. https://doi.org/10.3109/03639049209040898.

    Article  CAS  Google Scholar 

  20. Bourret E, Ratsimbazafy V, Maury L, Brossard C. Rheological behaviour of saturated polyglycolysed glycerides. J Pharm Pharmacol. 1994;46(7):538–41.

    Article  CAS  PubMed  Google Scholar 

  21. Wong LP, Gilligan CA, Po ALW. Preparation and characterization of sustained-release ibuprofen-cetostearyl alcohol spheres. Int J Pharm. 1992;83(1–3):95–114.

    Article  CAS  Google Scholar 

  22. Khan N, Craig DQM. Role of blooming in determining the storage stability of lipid-based dosage forms. J Pharm Sci. 2004;93(12):2962–71. https://doi.org/10.1002/jps.20210.

    Article  CAS  PubMed  Google Scholar 

  23. Ofori-Kwakye K, Mfoafo KA, Kipo SL, Kuntworbe N, Boakye-Gyasi ME. Development and evaluation of natural gum-based extended release matrix tablets of two model drugs of different water solubilities by direct compression. Saudi Pharm J. 2016;24(1):82–91. https://doi.org/10.1016/j.jsps.2015.03.005.

    Article  PubMed  Google Scholar 

  24. Uchimoto T, Iwao Y, Takahashi K, Tanaka S, Agata Y, Iwamura T, et al. A comparative study of glycerin fatty acid ester and magnesium stearate on the dissolution of acetaminophen tablets using the analysis of available surface area. Eur J Pharm Biopharm. 2011;78(3):492–8. https://doi.org/10.1016/j.ejpb.2011.01.014.

    Article  CAS  PubMed  Google Scholar 

  25. Kumar PM, Ghosh A. Development and evaluation of metronidazole loaded microsponge based gel for superficial surgical wound infections. J Drug Deliv Sci Tech. 2015;30:15–29. https://doi.org/10.1016/j.jddst.2015.09.006.

    Article  CAS  Google Scholar 

  26. Polli JE, Rekhi GS, Augsburger LL, Shah VP. Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J Pharm Sci. 1997;86(6):690–700. https://doi.org/10.1021/Js960473x.

    Article  CAS  PubMed  Google Scholar 

  27. Costa P, Manuel J, Lobo S. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–33. https://doi.org/10.1016/S0928-0987(01)00095-1.

    Article  CAS  PubMed  Google Scholar 

  28. Reti-Nagy K, Malanga M, Fenyvesi E, Szente L, Vamosi G, Varadi J, et al. Endocytosis of fluorescent cyclodextrins by intestinal Caco-2 cells and its role in paclitaxel drug delivery. Int J Pharm. 2015;496(2):509–17. https://doi.org/10.1016/j.ijpharm.2015.10.049.

    Article  CAS  PubMed  Google Scholar 

  29. Cole ET, Cade D, Benameur H. Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration. Adv Drug Deliv Rev. 2008;60(6):747–56. https://doi.org/10.1016/j.addr.2007.09.009.

    Article  CAS  PubMed  Google Scholar 

  30. Lerk CF, Bolhuis GK, Deboer AH. Effect of microcrystalline cellulose on liquid penetration in and disintegration of directly compressed tablets. J Pharm Sci. 1979;68(2):205–11. https://doi.org/10.1002/jps.2600680222.

    Article  CAS  PubMed  Google Scholar 

  31. de los Santos CJJ, Perez-Martinez JI, Gomez-Pantoja ME, Moyano JR. Enhancement of albendazole dissolution properties using solid dispersions with Gelucire 50/13 and PEG 15000. J Drug Deliv Sci Tec. 2017;42:261–72. https://doi.org/10.1016/j.jddst.2017.03.030.

    Article  CAS  Google Scholar 

  32. Kalantzi L, Reppas C, Dressman JB, Amidon GL, Junginger HE, Midha KK, et al. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol). J Pharm Sci. 2006;95(1):4–14. https://doi.org/10.1002/jps.20477.

    Article  CAS  PubMed  Google Scholar 

  33. Ivanova BB. Monoclinic and orthorhombic polymorphs of paracetamol—solid state linear dichroic infrared spectral analysis. J Mol Struct. 2005;738(1–3):233–8. https://doi.org/10.1016/j.molstruc.2004.12.036.

    Article  CAS  Google Scholar 

  34. Wang IC, Lee MJ, Seo DY, Lee HE, Choi Y, Kim WS, et al. Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process. AAPS PharmSciTech. 2011;12(2):764–70. https://doi.org/10.1208/s12249-011-9642-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nair R, Vemuri M, Agrawala P, Kim SI. Investigation of various factors affecting encapsulation on the in-cap automatic capsule-filling machine. AAPS PharmSciTech. 2004;5(4):46–53.

    Article  PubMed Central  Google Scholar 

  36. Mei XH, Etzler FM, Wang Z. Use of texture analysis to study hydrophilic solvent effects on the mechanical properties of hard gelatin capsules. Int J Pharm. 2006;324(2):128–35. https://doi.org/10.1016/j.ijpharm.2006.06.017.

    Article  CAS  PubMed  Google Scholar 

  37. Kontny MJ, Mulski CA. Gelatin capsule brittleness as a function of relative-humidity at room-temperature. Int J Pharmaceut. 1989;54(1):79–85. https://doi.org/10.1016/0378-5173(89)90168-3.

    Article  CAS  Google Scholar 

  38. Szakonyi G, Zelko R. Prediction of oral disintegration time of fast disintegrating tablets using texture analyzer and computational optimization. Int J Pharm. 2013;448(2):346–53. https://doi.org/10.1016/j.ijpharm.2013.03.047.

    Article  CAS  PubMed  Google Scholar 

  39. Paradkar M, Gajra B, Patel B. Formulation development and evaluation of medicated chewing gum of anti-emetic drug. Saudi Pharmaceutical Journal. 2016;24(2):153–64. https://doi.org/10.1016/j.jsps.2015.02.017.

    Article  PubMed  Google Scholar 

  40. Qi S, Marchaud D, Craig DQM. An investigation into the mechanism of dissolution rate enhancement of poorly water-soluble drugs from spray chilled Gelucire 50/13 microspheres. J Pharm Sci. 2010;99(1):262–74. https://doi.org/10.1002/jps.21832.

    Article  CAS  PubMed  Google Scholar 

  41. Sutananta W, Craig DQM, Newton JM. The Effects of Aging on the Thermal-Behavior and Mechanical-Properties of Pharmaceutical Glycerides. Int J Pharmaceut. 1994;111(1):51–62. https://doi.org/10.1016/0378-5173(94)90401-4.

    Article  CAS  Google Scholar 

  42. Sutananta W, Craig DQM, Newton JM. An investigation into the effect of preparation conditions on the structure and mechanical-properties of pharmaceutical glyceride bases. Int J Pharmaceut. 1994;110(1):75–91. https://doi.org/10.1016/0378-5173(94)90377-8.

    Article  CAS  Google Scholar 

  43. Maniruzzaman M, Islam MT, Moradiya HG, Halsey SA, Slipper IJ, Chowdhry BZ, et al. Prediction of polymorphic transformations of paracetamol in solid dispersions. J Pharm Sci. 2014;103(6):1819–28. https://doi.org/10.1002/jps.23992.

    Article  CAS  PubMed  Google Scholar 

  44. Rediguieri CF, Porta V, G Nunes DS, Nunes TM, Junginger HE, Kopp S, et al. Biowaiver monographs for immediate release solid oral dosage forms: metronidazole. J Pharm Sci. 2011;100(5):1618–27. https://doi.org/10.1002/jps.22409.

    Article  CAS  PubMed  Google Scholar 

  45. Cavallari C, Rodriguez L, Albertini B, Passerini N, Rosetti F, Fini A. Thermal and fractal analysis microparticles obtained by of diclofenac/Gelucire 50/13 ultrasound-assisted atomization. J Pharm Sci. 2005;94(5):1124–34. https://doi.org/10.1002/Jps.20337.

    Article  CAS  PubMed  Google Scholar 

  46. Fini A, Moyano JR, Gines JM, Perez-Martinez JI, Rabasco AM. Diclofenac salts, II. Solid dispersions in PEG6000 and Gelucire 50/13. Eur J Pharm Biopharm. 2005;60(1):99–111. https://doi.org/10.1016/j.ejpb.2004.11.005.

    Article  CAS  PubMed  Google Scholar 

  47. Sutananta W, Craig DQM, Newton JM. An investigation into the effects of preparation conditions and storage on the rate of drug-release from pharmaceutical glyceride bases. J Pharm Pharmacol. 1995;47(5):355–9.

    Article  CAS  PubMed  Google Scholar 

  48. Choy YW, Khan N, Yuen KH. Significance of lipid matrix aging on in vitro release and in vivo bioavailability. Int J Pharm. 2005;299(1–2):55–64. https://doi.org/10.1016/j.ijpharm.2005.04.030.

    Article  CAS  PubMed  Google Scholar 

  49. Maheshwari M, Ketkar AR, Chauhan B, Patil VB, Paradkar AR. Preparation and characterization of ibuprofen-cetyl alcohol beads by melt solidification technique: effect of variables. Int J Pharm. 2003;261(1–2):57–67.

    Article  CAS  PubMed  Google Scholar 

  50. Miyagawa Y, Okabe T, Yamaguchi Y, Miyajima M, Sato H, Sunada H. Controlled-release of diclofenac sodium from wax matrix granule. Int J Pharmaceut. 1996;138(2):215–24. https://doi.org/10.1016/0378-5173(96)04547-4.

    Article  CAS  Google Scholar 

  51. Sutananta W, Craig DQM, Newton JM. An evaluation of the mechanisms of drug-release from glyceride bases. J Pharm Pharmacol. 1995;47(3):182–7.

    Article  CAS  PubMed  Google Scholar 

  52. O'Hara T, Dunne A, Butler J, Devane J. A review of methods used to compare dissolution profile data. Pharm Sci Technol Today. 1998;1(5):214–23. https://doi.org/10.1016/S1461-5347(98)00053-4.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Ágnes Hajdu from Azelis Hungary is acknowledged for providing the continuous contact with Gattefossé and suppling Gelucire samples. Last but not least, Erik Schwendtner from Colorcon Hungary is gratefully thanked for providing free sample and information about the applications of different Ethocel grades.

Funding

This paper was supported by the János Bolyai Research Scholarsip of the Hungarian Academy of sciences (BO/00290/16/5). The publication is supported by the EFOP-3.6.1-16-2016-00022 projects. The project is co-financed by the European Union and the European Social Fund. This research was also supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of GINOP-2.3.2-15-2016-00043.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Technology, University of Debrecen, Nagyerdei krt. 98., PO Box 78, Debrecen, 4010, Hungary

    Gábor Vasvári, Bence Csontos, Judit Váradi, Ildikó Bácskay, Zoltán Ujhelyi, Pálma Fehér, Dávid Sinka, Thi Le Phuong Nguyen, Miklós Vecsernyés & Ferenc Fenyvesi

  2. Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös u. 6., Szeged, 6720, Hungary

    Tamás Sovány & Géza Regdon Jr

  3. Department of Physical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary

    Attila Bényei

Authors
  1. Gábor Vasvári
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bence Csontos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tamás Sovány
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Géza Regdon Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Attila Bényei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Judit Váradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ildikó Bácskay
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zoltán Ujhelyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pálma Fehér
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dávid Sinka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thi Le Phuong Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Miklós Vecsernyés
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ferenc Fenyvesi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ferenc Fenyvesi.

Electronic Supplementary Material

ESM 1

(DOCX 14 kb)

ESM 2

(DOCX 12 kb)

Fig. S1

Diffractograms of the pure APIs, Gelucire 50/13 and the fresh DS1, ACP1 and MNZ1 matrices. A pure DS, B fresh DS1, C pure ACP, D fresh ACP1, E pure MNZ, F fresh MNZ1, G pure GC. The collected frames were integrated, the raw pXRD curves are ordered and their sizes were adjusted to match at the same degree of 2 Theta. (JPG 111 kb)

Fig. S2

HPLC assay chromatograms of the 2 years old DS matrices. Chromatograms of the 10× methanolic dilutions of the 2 years old A DS1, B DS2, C DS3. Impurity can be seen on A and B at 5.6 min. (JPG 228 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vasvári, G., Csontos, B., Sovány, T. et al. Development and Characterisation of Modified Release Hard Gelatin Capsules, Based on In Situ Lipid Matrix Formation. AAPS PharmSciTech 19, 3165–3176 (2018). https://doi.org/10.1208/s12249-018-1146-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-018-1146-5

KEY WORDS

Search

Navigation