AAPS PharmSciTech

, Volume 19, Issue 5, pp 2213–2225 | Cite as

Transfer Behavior of the Weakly Acidic BCS Class II Drug Valsartan from the Stomach to the Small Intestine During Fasted and Fed States

  • Rania HamedEmail author
  • Sabreen Hasan Alnadi
Research Article


The objective of this study was to investigate the transfer behavior of the weakly acidic BCS class II drug valsartan from the stomach to the small intestine during fasted and fed states. An in vitro transfer model previously introduced by Kostewicz et al. (J Pharm Pharmacol 56(1):43–51, 2004) based on a syringe pump and a USP paddle apparatus was used to determine the concentration profiles of valsartan in the small intestine. Donor phases of simulated gastric fluid during fasted (FaSSGF) and fed (FeSSGF) states were used to predisperse Diovan® tablets (160 mg valsartan). The initial concentrations of valsartan in FaSSGF and FeSSGF were 6.2 and 91.8%, respectively. Valsartan dispersions were then transferred to acceptor phases that simulate intestinal fluid and cover the physiological properties (pH, buffer capacity, and ionic strength) of the gastrointestinal fluid at a flow rate of 2 mL/min. The pH measurements were reported at time intervals corresponded to those of the transfer experiments to investigate the effect of percent dissolved of valsartan in the donor phase on lowering the pH of the acceptor phases. The f2 similarity test was used to compare the concentration profiles in the acceptor phases. In fasted state, the concentration of valsartan in the acceptor phases ranged between 33.1 and 89.4% after 240 min. Whereas in fed state, valsartan was fully dissolved in all acceptor phases within a range of 94.5–104.9% after 240 min. Therefore, the transfer model provides a useful screen for the concentrations of valsartan in the small intestine during fasted and fed states.


Transfer model Valsartan Weak acid BCS class II Fed state Fasted state 



The authors would like to thank Engineer Areej Kamal for her help in the transfer experiments.

Funding information

This project was financially supported by the Deanship of Academic Research and Graduate Studies at Al-Zaytoonah University of Jordan.


  1. 1.
    Kostewicz ES, Wunderlich M, Brauns U, Becker R, Bock T, Dressman JB. Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine. J Pharm Pharmacol. 2004;56(1):43–51.CrossRefPubMedGoogle Scholar
  2. 2.
    Ruff A, Fiolka T, Kostewicz ES. Prediction of ketoconazole absorption using an updated in vitro transfer model coupled to physiologically based pharmacokinetic modelling. Eur J Pharm Sci. 2017;100:42–55.CrossRefPubMedGoogle Scholar
  3. 3.
    Tsume Y, Amidon G, Takeuchi S. Dissolution effect of gastric and intestinal pH fora BCS class II drug, pioglitazone: new in vitro dissolution system to predict in vivo dissolution. J Bioequiv Availab. 2013;5(6):224–7.CrossRefGoogle Scholar
  4. 4.
    Tsume Y, Takeuchi S, Matsui K, Amidon GE, Amidon GL. In vitro dissolution methodology, mini-gastrointestinal simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib. Eur J Pharm Sci. 2015;76:203–12.CrossRefPubMedGoogle Scholar
  5. 5.
    Wagner C, Jantratid E, Kesisoglou F, Vertzoni M, Reppas C, Dressman JB. Predicting the oral absorption of a poorly soluble, poorly permeable weak base using biorelevant dissolution and transfer model tests coupled with a physiologically based pharmacokinetic model. Eur J Pharm Biopharm. 2012;82(1):127–38.CrossRefPubMedGoogle Scholar
  6. 6.
    Klein S, Buchanan NL, Buchanan CM. Miniaturized transfer models to predict the precipitation of poorly soluble weak bases upon entry into the small intestine. AAPS PharmSciTech. 2012;13(4):1230–5.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Van Den Abeele J, Brouwers J, Mattheus R, Tack J, Augustijns P. Gastrointestinal behavior of weakly acidic BCS class II drugs in man—case study of diclofenac potassium. J Pharm Sci. 2016;105(2):687–96.CrossRefGoogle Scholar
  8. 8.
    Okumu A, DiMaso M, Löbenberg R. Computer simulations using GastroPlus™ to justify a biowaiver for etoricoxib solid oral drug products. Eur J Pharm Biopharm. 2009;72(1):91–8.CrossRefPubMedGoogle Scholar
  9. 9.
    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
  10. 10.
    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
  11. 11.
    Lindahl A, Ungell A-L, Knutson L, Lennernäs H. Characterization of fluids from the stomach and proximal jejunum in men and women. Pharm Res. 1997;14(4):497–502.CrossRefPubMedGoogle Scholar
  12. 12.
    Bergström CA, Holm R, Jørgensen SA, Andersson SB, Artursson P, Beato S, et al. Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs. Eur J Pharm Sci. 2014;57:173–99.CrossRefPubMedGoogle Scholar
  13. 13.
    Kalantzi L, Goumas K, Kalioras V, Abrahamsson B, Dressman JB, Reppas C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharm Res. 2006;23(1):165–76.CrossRefPubMedGoogle Scholar
  14. 14.
    Johnson J, Holinej J, Williams M. Influence of ionic strength on matrix integrity and drug release from hydroxypropyl cellulose compacts. Int J Pharm. 1993;90(2):151–9.CrossRefGoogle Scholar
  15. 15.
    Persson EM, Gustafsson A-S, Carlsson AS, Nilsson RG, Knutson L, Forsell P, et al. The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids. Pharm Res. 2005;22(12):2141–51.CrossRefPubMedGoogle Scholar
  16. 16.
    Hens B, Tsume Y, Bermejo M, Paixao P, Koenigsknecht MJ, Baker JR, et al. Low buffer capacity and alternating motility along the human gastrointestinal tract: implications for in vivo dissolution and absorption of Ionizable drugs. Mol Pharm. 2017;14(12):4281–94.CrossRefPubMedGoogle Scholar
  17. 17.
    Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res. 2008;25(7):1663–76.CrossRefPubMedGoogle Scholar
  18. 18.
    Klein S, Wempe MF, Zoeller T, Buchanan NL, Lambert JL, Ramsey MG, et al. Improving glyburide solubility and dissolution by complexation with hydroxybutenyl-beta-cyclodextrin. J Pharm Pharmacol. 2009;61(1):23–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Hamed R, Awadallah A, Sunoqrot S, Tarawneh O, Nazzal S, AlBaraghthi T, et al. pH-dependent solubility and dissolution behavior of carvedilol—case example of a weakly basic BCS class II drug. AAPS PharmSciTech. 2016;17(2):418–26.CrossRefPubMedGoogle Scholar
  20. 20.
    Asare-Addo K, Conway BR, Larhrib H, Levina M, Rajabi-Siahboomi AR, Tetteh J, et al. The effect of pH and ionic strength of dissolution media on in-vitro release of two model drugs of different solubilities from HPMC matrices. Colloids Surf B. 2013;111:384–91.CrossRefGoogle Scholar
  21. 21.
    Jamzad S, Fassihi R. Role of surfactant and pH on dissolution properties of fenofibrate and glipizide—a technical note. AAPS PharmSciTech. 2006;7(2):E33–E.CrossRefPubMedGoogle Scholar
  22. 22.
    Costa P, Manuel J, Lobo S. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–33.CrossRefPubMedGoogle Scholar
  23. 23.
    Diaz DA, Colgan ST, Langer CS, Bandi NT, Likar MD, Van Alstine L. Dissolution similarity requirements: how similar or dissimilar are the global regulatory expectations? AAPS J. 2016;18(1):15–22.CrossRefPubMedGoogle Scholar
  24. 24.
    Fuchs A, Leigh M, Kloefer B, Dressman JB. Advances in the design of fasted state simulating intestinal fluids: FaSSIF-V3. Eur J Pharm Biopharm. 2015;94:229–40.CrossRefPubMedGoogle Scholar
  25. 25.
    Leigh M, Kloefer B, Schaich M. Comparison of the solubility and dissolution of drugs in fasted-state biorelevant media (FaSSIF and FaSSIF-V2). Dissolut Technol. 2013;20(3):44–50.CrossRefGoogle Scholar
  26. 26.
    Ghazal HS, Dyas AM, Ford JL, Hutcheon GA. In vitro evaluation of the dissolution behaviour of itraconazole in bio-relevant media. Int J Pharm. 2009;366(1–2):117–23.CrossRefPubMedGoogle Scholar
  27. 27.
    Stippler ES, Romero NE, Mauger JW. Formulating buffered dissolution media for sparingly soluble weak acid and weak base drug compounds based on microenvironmental pHo considerations. Dissolut Technol. 2014;21(4):20–5.CrossRefGoogle Scholar
  28. 28.
    Ozturk SS, Palsson BO, Dressman JB. Dissolution of ionizable drugs in buffered and unbuffered solutions. Pharm Res. 1988;5(5):272–82.CrossRefPubMedGoogle Scholar
  29. 29.
    Sa’ib JK. Titrimetric study of the solubility and dissociation of benzoic acid in water: effect of ionic strength and temperature. Am J Anal Chem. 2015;6(05):429.CrossRefGoogle Scholar
  30. 30.
    Takács-Novák K, Szőke V, Völgyi G, Horváth P, Ambrus R, Szabó-Révész P. Biorelevant solubility of poorly soluble drugs: rivaroxaban, furosemide, papaverine and niflumic acid. J Pharm Biomed Anal. 2013;83:279–85.CrossRefPubMedGoogle Scholar
  31. 31.
    Guideline IHT, editor. Validation of analytical procedures: text and methodology Q2 (R1). International Conference on Harmonization, Geneva, Switzerland; 2005.Google Scholar
  32. 32.
    Worsøe J, Fynne L, Gregersen T, Schlageter V, Christensen LA, Dahlerup JF, et al. Gastric transit and small intestinal transit time and motility assessed by a magnet tracking system. BMC Gastroenterol. 2011;11(1):145.CrossRefPubMedGoogle Scholar
  33. 33.
    Fadda HM, McConnell EL, Short MD, Basit AW. Meal-induced acceleration of tablet transit through the human small intestine. Pharm Res. 2009;26(2):356–60.CrossRefPubMedGoogle Scholar
  34. 34.
    Corrigan OI, Devlin Y, Butler J. Influence of dissolution medium buffer composition on ketoprofen release from ER products and in vitro–in vivo correlation. Int J Pharm. 2003;254(2):147–54.CrossRefPubMedGoogle Scholar
  35. 35.
    Gowthamarajan K, Singh SK. Dissolution testing for poorly soluble drugs: a continuing perspective. Dissolut Technol. 2010;17(3):24–32.CrossRefGoogle Scholar
  36. 36.
    Yeom DW, Chae BR, Son HY, Kim JH, Chae JS, Song SH, et al. Enhanced oral bioavailability of valsartan using a polymer-based supersaturable self-microemulsifying drug delivery system. Int J Nanomedicine. 2017;12:3533–45.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Department of Pharmacy, Faculty of PharmacyAl-Zaytoonah University of JordanAmmanJordan

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