Skip to main content

Advertisement

SpringerLink
Log in

Sustained-release amorphous solid dispersions

  • Review Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

The use of amorphous solid dispersions (ASD) to overcome poor drug solubility has gained interest in the pharmaceutical industry over the past decade. ASDs are challenging to formulate because they are thermodynamically unstable, and the dispersed drugs tend to recrystallize. Until now, most research on ASDs has focused on immediate-release formulations, supersaturation, and stability; only a few studies have recently reported on the manufacturing of sustained-release ASDs. Sustained-release ASDs can minimize the frequency of administration and prevent high concentrations that can lead to toxicity. Sustained-release ASDs can also decrease the reprecipitation rate in the medium, which can lead to increased bioavailability. However, sustained-release ASDs also pose some significant challenges, such as intramatrix recrystallization, inhibition of drug release as a result of drug–polymer gelling, and low supersaturation due to a slow dissolution rate. This review details the challenges and the formulation approaches that have been investigated to manufacture sustained-release ASDs. In particular, the advantages and drawbacks of hydrophilic polymers, hydrophobic polymers, and lipid-based systems are discussed.

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

Similar content being viewed by others

References

  1. Siew A. Solving poor solubility to unlock a drug’s potential. Pharm Technol. 2015;39:20–7.

    Google Scholar 

  2. Serajuddin AT. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59(7):603–16.

    Article  CAS  PubMed  Google Scholar 

  3. Good DJ, Rodríguez-Hornedo NR. Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des. 2009;9:2252–64.

    Article  CAS  Google Scholar 

  4. Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006;29(3–4):278–87.

    Article  CAS  PubMed  Google Scholar 

  5. Dahan A, Miller JM, Hoffman A, Amidon GE, Amidon GL. The solubility-permeability interplay in using cyclodextrins as pharmaceutical solubilizers: mechanistic modeling and application to progesterone. J Pharm Sci. 2010;99(6):2739–49.

    Article  CAS  PubMed  Google Scholar 

  6. Shah N, Sandhu H, Phuapradit W, Pinal R, Iyer R, Albano A, et al. Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs. Int J Pharm. 2012;438(1–2):53–60.

    Article  CAS  PubMed  Google Scholar 

  7. Chiou WL, Riegelman S. Oral absorption of griseofulvin in dogs: increased absorption via solid dispersion in polyethylene glycol 6000. J Pharm Sci. 1970;59(7):937–42.

    Article  CAS  PubMed  Google Scholar 

  8. Serajuddin AT. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88(10):1058–66.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Miller JM, Beig A, Carr RA, Spence JK, Dahan A. A win-win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability. Mol Pharm. 2012;9(7):2009–16.

    Article  CAS  PubMed  Google Scholar 

  11. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm. 2002;54(2):107–17.

    Article  CAS  PubMed  Google Scholar 

  14. Taylor LS, Zhang GG. Physical chemistry of supersaturated solutions and implications for oral absorption. Adv Drug Deliv Rev. 2016;101:122–42.

    Article  CAS  PubMed  Google Scholar 

  15. Sun DD, Lee PI. Evolution of supersaturation of amorphous pharmaceuticals: the effect of rate of supersaturation generation. Mol Pharm. 2013;10(11):4330–46.

    Article  CAS  PubMed  Google Scholar 

  16. Colombo P. Swelling-controlled release in hydrogel matrices for oral route. Adv Drug Deliv Rev. 1993;11:37–57.

    Article  CAS  Google Scholar 

  17. Siepmann J, Siepmann F. Modeling of diffusion controlled drug delivery. J Control Release. 2012;161(2):351–62.

    Article  CAS  PubMed  Google Scholar 

  18. Nguyen TN, Tran PH, Van Vo T, Duan W, Truong-Dinh Tran T. Development of a sustained release solid dispersion using swellable polymer by melting method. Pharm Res. 2016;33(1):102–9.

    Article  CAS  PubMed  Google Scholar 

  19. LaFountaine JS, Prasad LK, Miller DA, McGinity JW, Williams RO 3rd. Mucoadhesive amorphous solid dispersions for sustained release of poorly water soluble drugs. Eur J Pharm Biopharm. 2017;113:157–67.

    Article  CAS  PubMed  Google Scholar 

  20. Tres F, Treacher K, Booth J, Hughes LP, Wren SA, Aylott JW, et al. Indomethacin-Kollidon VA64 extrudates: a mechanistic study of pH-dependent controlled release. Mol Pharm. 2016;13(3):1166–75.

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Debenedetti PB. Metastable liquids: concepts and principles. Princeton: Princeton University Press; 1996.

    Google Scholar 

  23. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1–3):3–26.

    Article  CAS  PubMed  Google Scholar 

  24. Dokoumetzidis A, Macheras P. A century of dissolution research: from Noyes and Whitney to the biopharmaceutics classification system. Int J Pharm. 2006;321(1–2):1–11.

    Article  CAS  PubMed  Google Scholar 

  25. Janssens S, Van den Mooter G. Review: physical chemistry of solid dispersions. J Pharm Pharmacol. 2009;61(12):1571–86.

    Article  CAS  PubMed  Google Scholar 

  26. LaMer V, Dinegar R. Theory, production and mechanism of formation of monodispersed hydrosols. J Am Chem Soc. 1950;72:4847–54.

    Article  CAS  Google Scholar 

  27. 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 

  28. Hilden LR, Morris KR. Physics of amorphous solids. J Pharm Sci. 2004;93(1):3–12.

    Article  CAS  PubMed  Google Scholar 

  29. Hancock BC, Shamblin SL, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res. 1995;12(6):799–806.

    Article  CAS  PubMed  Google Scholar 

  30. Chokshi RJ, Shah NH, Sandhu HK, Malick AW, Zia H. Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration. J Pharm Sci. 2008;97(6):2286–98.

    Article  CAS  PubMed  Google Scholar 

  31. Vasanthavada M, Tong WQ, Joshi Y, Kislalioglu MS. Phase behavior of amorphous molecular dispersions I: determination of the degree and mechanism of solid solubility. Pharm Res. 2004;21(9):1598–606.

    Article  CAS  PubMed  Google Scholar 

  32. Wang X, Michoel A, Van den Mooter G. Solid state characteristics of ternary solid dispersions composed of PVP VA64, Myrj 52 and itraconazole. Int J Pharm. 2005;303(1–2):54–61.

    Article  CAS  PubMed  Google Scholar 

  33. Siepmann J, Siepmann F. Mathematical modeling of drug delivery. Int J Pharm. 2008;364(2):328–43.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Verma S, Rudraraju VS. Disintegration mediated controlled release supersaturating solid dispersion formulation of an insoluble drug: design, development, optimization, and in vitro evaluation. AAPS PharmSciTech. 2015;16(1):85–97.

    Article  CAS  PubMed  Google Scholar 

  36. Goepferich A. Mechanisms of polymer degradation and erosion. Biomaterials. 1996;17:103–14.

    Article  CAS  Google Scholar 

  37. Pokharkar VB, Mandpe LP, Padamwar MN, Ambike AA, Mahadik RK, Paradkar A. Development, characterization and stabilization of amorphous form of a low Tg drug. Powder Technol. 2006;167(1):20–5.

    Article  CAS  Google Scholar 

  38. Tajarobi F, Larsson A, Matic H, Abrahmsen-Alami S. The influence of crystallization inhibition of HPMC and HPMCAS on model substance dissolution and release in swellable matrix tablets. Eur J Pharm Biopharm. 2011;78(1):125–33.

    Article  CAS  PubMed  Google Scholar 

  39. Fan C, Pai-Thakur R, Phuapradit W, Zhang L, Tian H, Malick W, et al. Impact of polymers on dissolution performance of an amorphous gelleable drug from surface-coated beads. Eur J Pharm Sci. 2009;37(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  40. Alderman D. A review of cellulose ethers in hydrophilic matrices for oral controlled-release dosage forms. Int J Pharm Technol Prod Manuf. 1984;5(3):1–9.

    CAS  Google Scholar 

  41. Sun DD, Lee PI. Probing the mechanisms of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers. J Control Release. 2015;211:85–93.

    Article  CAS  PubMed  Google Scholar 

  42. Sun DD, Ju TC, Lee PI. Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels. Eur J Pharm Biopharm. 2012;81(1):149–58.

    Article  CAS  PubMed  Google Scholar 

  43. Meng F, Meckel J, Zhang F. Investigation of itraconazole ternary amorphous solid dispersions based on povidone and Carbopol. Eur J Pharm Sci. 2017;106:413–21.

    Article  CAS  PubMed  Google Scholar 

  44. Demuth B, Nagy ZK, Balogh A, Vigh T, Marosi G, Verreck G, et al. Downstream processing of polymer-based amorphous solid dispersions to generate tablet formulations. Int J Pharm. 2015;486(1–2):268–86.

    Article  CAS  PubMed  Google Scholar 

  45. Jijun F, Lishuang X, Xiaoli W, Shu Z, Xiaoguang T, Xingna Z, et al. Nimodipine (NM) tablets with high dissolution containing NM solid dispersions prepared by hot-melt extrusion. Drug Dev Ind Pharm. 2011;37(8):934–44.

    Article  PubMed  CAS  Google Scholar 

  46. Nemet Z, Sztatisz J, Demeter A. Polymorph transitions of bicalutamide: a remarkable example of mechanical activation. J Pharm Sci. 2008;97(8):3222–32.

    Article  CAS  PubMed  Google Scholar 

  47. Leane MM, Sinclair W, Qian F, Haddadin R, Brown A, Tobyn M, et al. Formulation and process design for a solid dosage form containing a spray-dried amorphous dispersion of ibipinabant. Pharm Dev Technol. 2013;18(2):359–66.

    Article  CAS  PubMed  Google Scholar 

  48. Finch CA. Hydrophilic polymers. In: Dyson RW, editor. Specialty polymers. Springer US; 1987. p. 65–82.

  49. Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today. 2007;12(23–24):1068–75.

    Article  CAS  PubMed  Google Scholar 

  50. Li CL, Martini LG, Ford JL, Roberts M. The use of hypromellose in oral drug delivery. J Pharm Pharmacol. 2005;57(5):533–46.

    Article  CAS  PubMed  Google Scholar 

  51. Rogers TL. Hypromellose. In: Rowe RC, Sheskey PJ, Quinn ME, editors. Handbook of pharmaceutical excipients. 6th ed. London: Pharmaceutical Press; 2009. p. 326–9.

    Google Scholar 

  52. Six K, Daems T, de Hoon J, Van Hecken A, Depre M, Bouche MP, et al. Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion. Eur J Pharm Sci. 2005;24(2–3):179–86.

    Article  CAS  PubMed  Google Scholar 

  53. Paaver U, Heinamaki J, Laidmae I, Lust A, Kozlova J, Sillaste E, et al. Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs. Int J Pharm. 2015;479(1):252–60.

    Article  CAS  PubMed  Google Scholar 

  54. Sheth AR, Bates S, Muller FX, Grant DJW. Polymorphism in piroxicam. Cryst Growth Des. 2004;4:1091–8.

    Article  CAS  Google Scholar 

  55. Shergill M, Patel M, Khan S, Bashir A, McConville C. Development and characterisation of sustained release solid dispersion oral tablets containing the poorly water soluble drug disulfiram. Int J Pharm. 2016;497(1–2):3–11.

    Article  CAS  PubMed  Google Scholar 

  56. Lee H-J, Kim J-Y, Park S-H, Rhee Y-S, Park C-W, Park E-S. Controlled-release oral dosage forms containing nimodipine solid dispersion and hydrophilic carriers. J Drug Deliv Sci Technol. 37:28–37.

  57. Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2001;48(2–3):139–57.

    Article  CAS  PubMed  Google Scholar 

  58. Lu Z, Yang Y, Covington RA, Bi YV, Durig T, Ilies MA, et al. Supersaturated controlled release matrix using amorphous dispersions of glipizide. Int J Pharm. 2016;511(2):957–68.

    Article  CAS  PubMed  Google Scholar 

  59. Lu Z, Yang Y, Covington RA, Bi YV, Durig T, Fassihi R. Amorphous-based controlled-release gliclazide matrix system. AAPS PharmSciTech. 2016;18(5):1699–709.

    Article  PubMed  CAS  Google Scholar 

  60. Tran PH, Tran TT, Piao ZZ, Vo TV, Park JB, Lim J, et al. Physical properties and in vivo bioavailability in human volunteers of isradipine using controlled release matrix tablet containing self-emulsifying solid dispersion. Int J Pharm. 2013;450(1–2):79–86.

    Article  CAS  PubMed  Google Scholar 

  61. Lin Q, Fu Y, Li J, Qu M, Deng L, Gong T, et al. A (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer)-dispersed sustained-release tablet for imperialine to simultaneously prolong the drug release and improve the oral bioavailability. Eur J Pharm Sci. 2015;79:44–52.

    Article  CAS  PubMed  Google Scholar 

  62. Tran HT, Park JB, Hong KH, Choi HG, Han HK, Lee J, et al. Preparation and characterization of pH-independent sustained release tablet containing solid dispersion granules of a poorly water-soluble drug. Int J Pharm. 2011;415(1–2):83–8.

    Article  CAS  PubMed  Google Scholar 

  63. Draganoiu E, Rajabi-Siahboomi A, Tiwari S. Carbomer. In: Rowe RC, Sheskey PJ, Quinn ME, editors. Handbook of pharmaceutical excipients. 6th ed. London: Pharmaceutical Press; 2009. p. 110–4.

    Google Scholar 

  64. Sun DD, Lee PI. Crosslinked hydrogels—a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs. Acta Pharm Sin B. 2014;4(1):26–36.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Law KY. Definitions for hydrophilicity, hydrophobicity, and superhydrophobicity: getting the basics right. J Phys Chem Lett. 2014;5(4):686–8.

    Article  CAS  PubMed  Google Scholar 

  66. Desai J, Alexander K, Riga A. Characterization of polymeric dispersions of dimenhydrinate in ethyl cellulose for controlled release. Int J Pharm. 2006;308(1–2):115–23.

    Article  CAS  PubMed  Google Scholar 

  67. Snejdrova E, Drastik M, Dittrich M, Kastner P, Nguyenova J. Mucoadhesive plasticized system of branched poly(lactic-co-glycolic acid) with aciclovir. Drug Dev Ind Pharm. 2016;42(10):1653–9.

    Article  CAS  PubMed  Google Scholar 

  68. Dang N, Sivakumaran H, Harrich D, Shaw PN, Coombes AG. Evaluation of polycaprolactone matrices for sustained vaginal delivery of nevirapine in the prevention of heterosexual HIV transmission. J Pharm Sci. 2014;103(7):2107–15.

    Article  CAS  PubMed  Google Scholar 

  69. Jannin V, Rodier JD, Musakhanian J. Polyoxylglycerides and glycerides: effects of manufacturing parameters on API stability, excipient functionality and processing. Int J Pharm. 2014;466(1–2):109–21.

    Article  CAS  PubMed  Google Scholar 

  70. Lu M, Xiong D, Sun W, Yu T, Hu Z, Ding J, et al. Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation. Drug Deliv. 2017;24(1):622–31.

    Article  CAS  PubMed  Google Scholar 

  71. Shah NV, Seth AK, Balaraman R, Aundhia CJ, Maheshwari RA, Parmar GR. Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: design and in vivo study. J Adv Res. 2016;7(3):423–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Liu Y, Salituro GM, Lee KJ, Bak A, Leung DH. Modulating drug release and enhancing the oral bioavailability of torcetrapib with solid lipid dispersion formulations. AAPS PharmSciTech. 2015;16(5):1091–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, A1920, Austin, TX, 78712, USA

    Julien Maincent & Robert O. Williams III

Authors
  1. Julien Maincent
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert O. Williams III
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert O. Williams III.

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

Maincent, J., Williams, R.O. Sustained-release amorphous solid dispersions. Drug Deliv. and Transl. Res. 8, 1714–1725 (2018). https://doi.org/10.1007/s13346-018-0494-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-018-0494-8

Keywords

Search

Navigation