AAPS PharmSciTech

, Volume 18, Issue 8, pp 2841–2853 | Cite as

Biomimetic Dissolution: A Tool to Predict Amorphous Solid Dispersion Performance

  • Michael M. Puppolo
  • Justin R. Hughey
  • Traciann Dillon
  • David Storey
  • Susan Jansen-Varnum
Review Article


The presented study describes the development of a membrane permeation non-sink dissolution method that can provide analysis of complete drug speciation and emulate the in vivo performance of poorly water-soluble Biopharmaceutical Classification System class II compounds. The designed membrane permeation methodology permits evaluation of free/dissolved/unbound drug from amorphous solid dispersion formulations with the use of a two-cell apparatus, biorelevant dissolution media, and a biomimetic polymer membrane. It offers insight into oral drug dissolution, permeation, and absorption. Amorphous solid dispersions of felodipine were prepared by hot melt extrusion and spray drying techniques and evaluated for in vitro performance. Prior to ranking performance of extruded and spray-dried felodipine solid dispersions, optimization of the dissolution methodology was performed for parameters such as agitation rate, membrane type, and membrane pore size. The particle size and zeta potential were analyzed during dissolution experiments to understand drug/polymer speciation and supersaturation sustainment of felodipine solid dispersions. Bland-Altman analysis was performed to measure the agreement or equivalence between dissolution profiles acquired using polymer membranes and porcine intestines and to establish the biomimetic nature of the treated polymer membranes. The utility of the membrane permeation dissolution methodology is seen during the evaluation of felodipine solid dispersions produced by spray drying and hot melt extrusion. The membrane permeation dissolution methodology can suggest formulation performance and be employed as a screening tool for selection of candidates to move forward to pharmacokinetic studies. Furthermore, the presented model is a cost-effective technique.


free drug bioavailability membrane permeation dissolution amorphous solid dispersion poorly water soluble 



The authors wish to gratefully acknowledge the financial support of Hovione LLC. The authors would also like to thank Dr. Bruce Weber for his critical review of this manuscript.


  1. 1.
    Dahan A, Hoffman A. The effect of different lipid based formulations on the oral absorption of lipophilic drugs: the ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats. Eur J Pharm Biopharm. 2007;67(1):96–105.CrossRefPubMedGoogle Scholar
  2. 2.
    Dahan A, Miller JM. The solubility–permeability interplay and its implications in formulation design and development for poorly soluble drugs. AAPS J. 2012;14(2):244–51.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gao Y, Carr RA, Spence JK, Wang WW, Turner TM, Lipari JM, et al. A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: application to physiologically based pharmacokinetic modeling. Mol Pharm. 2010;7(5):1516–26.CrossRefPubMedGoogle Scholar
  4. 4.
    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. 2012;64:4–17.CrossRefGoogle Scholar
  5. 5.
    Hughey JR. Chapter 12: dissolution of stabilized amorphous drug formulations. Poorly soluble drugs: dissolution and drug release: Pan Stanford Publishing; 2017. p. 393–418.Google Scholar
  6. 6.
    O’Donnell KP, Williams III RO. Optimizing the formulation of poorly water-soluble drugs. Formulating poorly water soluble drugs: Springer; 2012. p. 27–93.Google Scholar
  7. 7.
    Thayer AM. Finding solutions. Chemical & Engineering News. 2010;88(22):13–8.CrossRefGoogle Scholar
  8. 8.
    Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res. 1998;15(1):11–22.CrossRefPubMedGoogle Scholar
  9. 9.
    Azarmi S, Roa W, Löbenberg R. Current perspectives in dissolution testing of conventional and novel dosage forms. Int J Pharm. 2007;328(1):12–21.CrossRefPubMedGoogle Scholar
  10. 10.
    Amidon GL, Sinko PJ, Fleisher D. Estimating human oral fraction dose absorbed: a correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm Res. 1988;5(10):651–4.CrossRefPubMedGoogle Scholar
  11. 11.
    Tsume Y, Mudie DM, Langguth P, Amidon GE, Amidon GL. The Biopharmaceutics Classification System: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC. Eur J Pharm Sci. 2014;57:152–63.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gautschi JT. Nonsink in vitro dissolution testing of amorphous solid dispersions. Melt extrusion: Springer; 2013. p. 205–20.Google Scholar
  13. 13.
    Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo W, Nightingale J. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008;5(6):1003–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Wu B, Li J, Wang Y. Evaluation of the microcentrifuge dissolution method as a tool for spray-dried dispersion. AAPS J. 2016;18(2):346–53.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kuentz M. Analytical technologies for real-time drug dissolution and precipitation testing on a small scale. J Pharm Pharmacol. 2015;67(2):143–59.CrossRefPubMedGoogle Scholar
  16. 16.
    Curatolo W, Nightingale JA, Herbig SM. Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res. 2009;26(6):1419–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Wallace SJ, Li J, Nation RL, Boyd BJ. Drug release from nanomedicines: selection of appropriate encapsulation and release methodology. Drug Deliv Transl Res. 2012;2(4):284–92.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    McAllister M. Dynamic dissolution: a step closer to predictive dissolution testing? Mol Pharm. 2010;7(5):1374–87.CrossRefPubMedGoogle Scholar
  19. 19.
    Fyfe C, Grondey H, Blazek-Welsh A, Chopra S, Fahie B. NMR imaging investigations of drug delivery devices using a flow-through USP dissolution apparatus. J Control Release. 2000;68(1):73–83.CrossRefPubMedGoogle Scholar
  20. 20.
    Hong J, Shah JC, Mcgonagle MD. Effect of cyclodextrin derivation and amorphous state of complex on accelerated degradation of ziprasidone. J Pharm Sci. 2011;100(7):2703–16.CrossRefPubMedGoogle Scholar
  21. 21.
    Phillips DJ, Pygall SR, Cooper VB, Mann JC. Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems. J Pharm Pharmacol. 2012;64(11):1549–59.CrossRefPubMedGoogle Scholar
  22. 22.
    Shi Y, Gao P, Gong Y, Ping H. Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption. Mol Pharm. 2010;7(5):1458–65.CrossRefPubMedGoogle Scholar
  23. 23.
    Phillips DJ, Pygall SR, Cooper VB, Mann JC. Toward biorelevant dissolution: application of a biphasic dissolution model as a discriminating tool for HPMC matrices containing a model BCS class II drug. Dissolution Technol. 2012;19(1):25–34.CrossRefGoogle Scholar
  24. 24.
    Alonzo DE, Gao Y, Zhou D, Mo H, Zhang GG, Taylor LS. Dissolution and precipitation behavior of amorphous solid dispersions. J Pharm Sci. 2011;100(8):3316–31.CrossRefPubMedGoogle Scholar
  25. 25.
    Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev. 2001;46(1):27–43.CrossRefPubMedGoogle Scholar
  26. 26.
    Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem. 1998;41(7):1007–10.CrossRefPubMedGoogle Scholar
  27. 27.
    Macheras P, Karalis V, Valsami G. Keeping a critical eye on the science and the regulation of oral drug absorption: a review. J Pharm Sci. 2013;102(9):3018–36.CrossRefPubMedGoogle Scholar
  28. 28.
    Obeso CG, Sousa MP, Song W, Rodriguez-Pérez MA, Bhushan B, Mano JF. Modification of paper using polyhydroxybutyrate to obtain biomimetic superhydrophobic substrates. Colloids Surf A Physicochem Eng Asp. 2013;416:51–5.CrossRefGoogle Scholar
  29. 29.
    Scholz A, Abrahamsson B, Diebold SM, Kostewicz E, Polentarutti BI, Ungell A-L, et al. Influence of hydrodynamics and particle size on the absorption of felodipine in labradors. Pharm Res. 2002;19(1):42–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Dailymed. Felodipine Extended Release Tablets. 2007.Google Scholar
  31. 31.
    van De Waterbeemd H, Camenisch G, Folkers G, Raevsky OA. Estimation of Caco-2 cell permeability using calculated molecular descriptors. Quantitative Structure-Activity Relationships. 1996;15(6):480–90.CrossRefGoogle Scholar
  32. 32.
    Shah N, Sandhu H, Choi DS, Chokshi H, Malick AW. Amorphous solid dispersions. Theory and practice: Springer; 2014.Google Scholar
  33. 33.
    Galia E, Nicolaides E, Hörter D, Löbenberg R, Reppas C, Dressman J. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res. 1998;15(5):698–705.CrossRefPubMedGoogle Scholar
  34. 34.
    Fagerberg JH, Tsinman O, Sun N, Tsinman K, Avdeef A, Bergström CA. Dissolution rate and apparent solubility of poorly soluble drugs in biorelevant dissolution media. Mol Pharm. 2010;7(5):1419–30.CrossRefPubMedGoogle Scholar
  35. 35.
    Reppas C, Vertzoni M. Biorelevant in-vitro performance testing of orally administered dosage forms. J Pharm Pharmacol. 2012;64(7):919–30.CrossRefPubMedGoogle Scholar
  36. 36.
    Vertzoni M, Fotaki N, Nicolaides E, Reppas C, Kostewicz E, Stippler E, et al. Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects. J Pharm Pharmacol. 2004;56(4):453–62.CrossRefPubMedGoogle Scholar
  37. 37.
    Lue B-M, Nielsen FS, Magnussen T, Schou HM, Kristensen K, Jacobsen LO, et al. Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound. Eur J Pharm Biopharm. 2008;69(2):648–57.CrossRefPubMedGoogle Scholar
  38. 38.
    Tang L, Khan SU, Muhammad NA. Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity. Pharm Dev Technol. 2001;6(4):531–40.CrossRefPubMedGoogle Scholar
  39. 39.
    Ross MH, Pawlina W. Histology: Lippincott Williams & Wilkins; 2006.Google Scholar
  40. 40.
    Simons K, Van Meer G. Lipid sorting in epithelial cells. Biochemistry. 1988;27(17):6197–202.CrossRefPubMedGoogle Scholar
  41. 41.
    Karlsson J, Artursson P. A method for the determination of cellular permeability coefficients and aqueous boundary layer thickness in monolayers of intestinal epithelial (Caco-2) cells grown in permeable filter chambers. Int J Pharm. 1991;71(1–2):55–64.CrossRefGoogle Scholar
  42. 42.
    Won D-H, Kim M-S, Lee S, Park J-S, Hwang S-J. Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process. Int J Pharm. 2005;301(1):199–208.CrossRefPubMedGoogle Scholar
  43. 43.
    Mu L, Feng S. Fabrication, characterization and in vitro release of paclitaxel (Taxol®) loaded poly (lactic-co-glycolic acid) microspheres prepared by spray drying technique with lipid/cholesterol emulsifiers. J Control Release. 2001;76(3):239–54.CrossRefPubMedGoogle Scholar
  44. 44.
    Riddick TM. Control of colloid stability through zeta potential. Blood. 1968;10(1).Google Scholar
  45. 45.
    Sugano K, Okazaki A, Sugimoto S, Tavornvipas S, Omura A, Mano T. Solubility and dissolution profile assessment in drug discovery. Drug Metab Pharmacokinet. 2007;22(4):225–54.CrossRefPubMedGoogle Scholar
  46. 46.
    Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol. 2002;42(6):620–43.CrossRefPubMedGoogle Scholar
  47. 47.
    Raina SA, Zhang GG, Alonzo DE, Wu J, Zhu D, Catron ND, et al. Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water-soluble drugs. J Pharm Sci. 2013.Google Scholar
  48. 48.
    Jackson MJ, Kestur US, Hussain MA, Taylor LS. Dissolution of danazol amorphous solid dispersions: supersaturation and phase behavior as a function of drug loading and polymer type. Mol Pharm. 2015;13(1):223–31.CrossRefPubMedGoogle Scholar
  49. 49.
    Nejdfors P, Ekelund M, Jeppsson B, Weström B. Mucosal in vitro permeability in the intestinal tract of the pig, the rat, and man: species-and region-related differences. Scand J Gastroenterol. 2000;35(5):501–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Bland JM, Altman D. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;327(8476):307–10.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Michael M. Puppolo
    • 1
    • 2
  • Justin R. Hughey
    • 3
  • Traciann Dillon
    • 1
  • David Storey
    • 1
  • Susan Jansen-Varnum
    • 2
  1. 1.Hovione LLCEast WindsorUSA
  2. 2.Department of ChemistryTemple UniversityPhiladelphiaUSA
  3. 3.Banner Life SciencesHigh PointUSA

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