Skip to main content

Advertisement

SpringerLink
Log in

Factors Affecting the Dissolution of Indomethacin Solid Dispersions

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

Abstract

The aim of this study was to investigate the influence of factors such as carrier type, drug/carrier ratio, binary carriers, and preparation method on the dissolution of an insoluble drug, indomethacin (IM), under supersaturation conditions. Using a solvent evaporation (SE) method, poloxamer 188 and PVP K30 showed better dissolution among the selected carriers. Furthermore, as the ratio of carriers increased (drug/carrier ratio from 1:0.5 to 1:2), the dissolution rate increased especially in almost two times poloxamer 188 solid dispersions (SDs), while the reverse results were observed for PVP K30 SDs. For the binary carrier SD, a lower dissolution was found. Under hot melt extrusion (HME), the dissolution of poloxamer 188 SD and PVP K30 SD was 0.83- and 0.94-folds lower than that using SE, respectively, while the binary carrier SD showed the best dissolution. For poloxamer 188 SDs, the drug’s crystal form changed when using SE, while no crystal form change was observed using HME. IM was amorphous in PVP K30 SDs prepared by both methods. For binary carrier systems, amorphous and crystalline drugs coexisted in SD using SE, and negligible amorphous IM was in SD using HME. This study indicated that a higher amorphous proportion in SD did not correlate with higher dissolution rate, and other factors, such as carrier type, particle size, and density, were also critical.

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
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16
Fig. 17
Fig. 18
Fig. 19
Fig. 20
Fig. 21

Similar content being viewed by others

References

  1. Vasconcelos T, Samento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today. 2008;39(25):1068–75.

    Google Scholar 

  2. Timpe C, Forschung L. Strategies for formulation development of poorly water-soluble drug candidates—a recent perspective. Am Pharm Rev. 2007;10:104–9.

    CAS  Google Scholar 

  3. Löbenberg R, Amidon G. Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur J Pharm Biopharm. 2000;50(1):3–12.

    Article  PubMed  Google Scholar 

  4. Sarode AL, Wang P, Obara S, Worthen DR. 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. 2014;86(3):351–60.

    Article  CAS  PubMed  Google Scholar 

  5. Bikiaris D. Solid dispersions, part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs. Expert Opin Drug Deliv. 2011;8(12):1663–80.

    Article  CAS  PubMed  Google Scholar 

  6. Alam MA, Ali R, FI AI-J, AL-Mohizea AM. Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates. Expert Opin Drug Deliv. 2012;9(11):1419–40.

    Article  CAS  PubMed  Google Scholar 

  7. Al-Obaidi H, Ke P, Brocchini S, Buckton B. Characterization and stability of ternary solid dispersions with PVP and PHPMA. Int J Pharm. 2011;419(1–2):20–7.

    Article  CAS  PubMed  Google Scholar 

  8. Martins RM, Siqueira S, Tacon LA, Freitas LAP. Microstructured ternary solid dispersions to improve carbamazepine solubility. Powder Technol. 2012;215(1):156–65.

    Article  Google Scholar 

  9. Mahmah O, Tabbakh R, Kelly A, Paradkar A. A comparative study of the effect of spray drying and hot-melt extrusion on the properties of amorphous solid dispersions containing felodipine. J Pharm Pharmacol. 2014;66(2):275–84.

    Article  CAS  PubMed  Google Scholar 

  10. Srinarong P, Waard HD, Frijlink HW, Hinrichs WLJ. Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations. Expert Opin Drug Deliv. 2011;8(9):1121–40.

    Article  CAS  PubMed  Google Scholar 

  11. Sethia S, Squillante E. Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods. Int J Pharm. 2004;272(1–2):1–10.

    Article  CAS  PubMed  Google Scholar 

  12. Patterson JE, James MB, Forster AH, Lancaster RW, Butler JM, Rades T. Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int J Pharm. 2007;336(1):22–34.

    Article  CAS  PubMed  Google Scholar 

  13. Dalsin MC, Tale S, Reineke TM. Solution-state polymer assemblies influence BCS class II drug dissolution and supersaturation maintenance. Biomacromolecules. 2014;15(2):500–11.

    Article  CAS  PubMed  Google Scholar 

  14. Newa M, Bhandari KH, Li DX, Kwon TH, Kim JA, Yoo BK, et al. Preparation, characterization and in vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188. Int J Pharm. 2007;343(1–2):228–37.

    Article  CAS  PubMed  Google Scholar 

  15. Maulvi FA, Dalwadi SJ, Thakkar VT, Soni TG, Gohel MC, Gandhi TR. Improvement of dissolution rate of aceclofenac by solid dispersion technique. Powder Technol. 2011;207(1–3):47–54.

    Article  CAS  Google Scholar 

  16. Newman A, Knipp G, Zografi G. Assessing the performance of amorphous solid dispersions. J Pharm Sci. 2012;101(4):1355–77.

    Article  CAS  PubMed  Google Scholar 

  17. Petralito S, Zanardi I, Memoli A, Cristina M, Millucci V, Travagli V. Apparent solubility and dissolution profile at non-sink conditions as quality improvement tools. Promising Pharmaceuticals. 2012;5:83–100.

    Google Scholar 

  18. Yamashita K, Nakate T, Okimoto K, Ohike A, Tokunaga Y, Ibuki R, et al. Establishment of new preparation method for solid dispersion formulation of tacrolimus. Int J Pharm. 2003;267(1–2):79–91.

    Article  CAS  PubMed  Google Scholar 

  19. Overhoff KA, Moreno A, Miller DA, Johnston KP, Williams RO III. Solid dispersions of itraconazole and enteric polymers made by ultra-rapid freezing. Int J Pharm. 2007;336(1):122–32.

    Article  CAS  PubMed  Google Scholar 

  20. Konno H, Handa T, Alonzo DE, Taylor LS. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm. 2008;70(2):493–9.

    Article  CAS  PubMed  Google Scholar 

  21. Valizadeh H, Nokhodchi A, Qarakhani N, Zakeri-Milani P, Azarmi S, Hassanzadeh D, et al. Physicochemical characterization of solid dispersions of indomethacin with PEG 6000, Myrj 52, lactose, sorbitol, dextrin, and Eudragit E100. Drug Dev Ind Pharm. 2004;30(3):303–17.

    Article  CAS  PubMed  Google Scholar 

  22. Rowe RC, Sheskey PJ, Quinn ME, editors. Handbook of pharmaceutical excipients. 6th ed. London: Pharmaceutical; 2009. p. 506–9.

    Google Scholar 

  23. Vippagunta SR, Maul KA, Tallavajhala S, Grant DJW. Solid state characterization of nifedipine solid dispersion. Int J Pharm. 2002;236(1–2):111–23.

    Article  CAS  PubMed  Google Scholar 

  24. Chokshi RJ, Sandhu HK, Iyer RM, Shah NH, Malick AW. Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution. J Pharm Sci. 2005;94(11):2463–74.

    Article  CAS  PubMed  Google Scholar 

  25. Yoshioka M, Hancock BC, Zografi G. Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipiatates. J Pharm Sci. 1995;84(8):983–6.

    Article  CAS  PubMed  Google Scholar 

  26. Sharma A, Jain CP. Preparation and characterization of solid dispersions of carvedilol with PVP K30. Res Pharm Sci. 2010;5(1):49–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Frizon F, Eloy JDO, Donaduzzi CM, Mitsui ML, Marchetti JM. Dissolution rate enhancement of loratadine in polyvinylpyrrolidone K-30 solid dispersions by solvent methods. Powder Technol. 2013;235:532–9.

    Article  CAS  Google Scholar 

  28. Taylor LS, Zografi G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res. 1997;14(12):1691–8.

    Article  CAS  PubMed  Google Scholar 

  29. Matsumoto T, Zografi G. Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly (vinylpyrrolidone-co-vinyl-acetate) in relation to indomethacin crystallization. Pharm Res. 1999;16(11):1722–8.

    Article  CAS  PubMed  Google Scholar 

  30. Otsuka M, Kato F, Matsuda Y. Determination of indomethacin polymorphic contents by chemometric near-infrared spectroscopy and conventional powder X-ray diffractometry. Analyst. 2001;126(9):1578–82.

    Article  CAS  PubMed  Google Scholar 

  31. Pan X, Julian T, Augsburger L. Quantitative measurement of indomethacin crystallinity in indomethacin-silica gel binary system using differential scanning calorimetry and X-ray powder diffractometry. AAPS Pharm Sci Tech. 2006;7(1):E72–8.

    Article  Google Scholar 

  32. Moghimi SM, Hunter AC, Dadswell CM, Savay S, Alving CR, Szebeni J. Causative factors behind poloxamer 188 (Pluronic F68, FlocorTM)-induced complement activation in human sera. A protective role against poloxamer-mediated complement activation by elevated serum lipoprotein levels. BBA-GEN Subjiects. 2004;1689(2):103–13.

    CAS  Google Scholar 

  33. Chutimaworapan S, Ritthidej GC, Yonemochi E, Oguchi T, Yamamoto K. Effect of water-soluble carriers on dissolution characteristics of nifedipine solid dispersions. Drug Dev Ind Pharm. 2000;26(11):1141–50.

    Article  CAS  PubMed  Google Scholar 

  34. Karavas E, Georgarakis E, Sigalas MP, Avgoustakis K, Bikiaris D. Investigation of the release mechanism of a sparingly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug-polymer interactions. Eur J Pharm Biopharm. 2007;66(3):334–47.

    Article  CAS  PubMed  Google Scholar 

  35. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Sci. 2000;50(1):47–60.

    CAS  Google Scholar 

  36. Craig DQM. 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 

  37. Paradkar A, Ambike AA, Jadhav BK, Mahadik KR. Characterization of curcumin-PVP solid dispersion obtained by spray drying. Int J Pharm. 2004;271(1–2):281–6.

    Article  CAS  PubMed  Google Scholar 

  38. Wang X, Michoel A, Mooter GV. Solid state characteristics of ternary solid dispersions composed of PVP VA64, Myrj 52 and itraconazole. Int J Pharm. 2005;303:54–61.

    Article  CAS  PubMed  Google Scholar 

  39. Janssens S, Nagels S, Armas HN, Autry WD, Schepdael AV, Mooter GV. Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVPVA 64, that were selected based on a supersaturation screening study. Eur J Pharm Biopharm. 2008;69:158–66.

    Article  CAS  PubMed  Google Scholar 

  40. Follonier N, Doelker E, Cole ET. Various ways of modulating the release of diltiazem hydrochloride from hot-melt extruded sustained release pellets prepared using polymeric materials. J Control Release. 1995;36(3):243–50.

    Article  CAS  Google Scholar 

  41. Andrews GP, Abu-Diak O, Kusmanto F, Homsby P, Hui Z, Jones DS. Physicochemical characterization and drug-release properties of celecoxib hot-melt extruded glass solutions. J Pharm Pharmacol. 2010;62(11):1580–90.

    Article  CAS  PubMed  Google Scholar 

  42. 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 

  43. Dong Z, Chatterji A, Sandhu H, Choi DS, Chokshi H, Shah N. Evaluation of solid state properties of solid dispersions prepared by hot-melt extrusion and solvent co-precipitation. Int J Pharm. 2008;355(1–2):141–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Professor Li Tong and Professor Wang Lihong for their helpful discussions. The Science and Technology Research and Development Project of Shiyan City in the year 2016 (No.: 16Y20) funded this work.

Author information

Authors and Affiliations

  1. Shanghai Aucta Pharma Co., Ltd., Room 301, Building #2, 3377 Kangxin Road, SIMZ Pudong, Shanghai, 201318, China

    Wei Zhang

  2. Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan, Hubei, 442000, People’s Republic of China

    Chen-ning Zhang, Yue He, Ban-yan Duan, Guang-yi Yang, Wei-dong Ma & Yong-hong Zhang

Authors
  1. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chen-ning Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yue He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ban-yan Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guang-yi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-dong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yong-hong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chen-ning Zhang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

The authors alone are responsible for the content and writing of the paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, W., Zhang, Cn., He, Y. et al. Factors Affecting the Dissolution of Indomethacin Solid Dispersions. AAPS PharmSciTech 18, 3258–3273 (2017). https://doi.org/10.1208/s12249-017-0813-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-017-0813-2

KEY WORDS

Search

Navigation