AAPS PharmSciTech

, Volume 19, Issue 7, pp 2898–2907 | Cite as

Using pH Gradient Dissolution with In-Situ Flux Measurement to Evaluate Bioavailability and DDI for Formulated Poorly Soluble Drug Products

  • Jane Li
  • Konstantin TsinmanEmail author
  • Oksana Tsinman
  • Larry Wigman
Research Article Theme: Advancements in Dissolution Testing of Oral and Non-Oral Formulations
Part of the following topical collections:
  1. Theme: Advancements in Dissolution Testing of Oral and Non-Oral Formulations


This study described a pH-gradient dissolution method combined with flux measurements as an in vitro tool for assessing the risk of bioavailability reduction due to drug-drug interactions (DDI) caused by acid reducing agents (ARAs). The device incorporates absorption chambers into USP II dissolution vessels, with fiber optic UV-probes monitoring concentration in situ. Dosage forms of Genentech BCS class II drugs, GDC-0810, GDC-0941, and compound A, were tested by starting the dissolution in either pH 1.6 or pH 4.0 media then converting to FaSSIF after 30 min. GDC-0810 showed no significant difference in flux between the two conversion experiments. A supersaturation phase was observed for GDC-0941 in the pH 1.6 experiments after media conversion to FaSSIF; however, it did not appear to occur in the pH 4.0 experiment due to low drug solubility at pH 4.0, resulting in a 95% decrease in flux compared to pH 1.6 experiment. The extent of flux reduction and the total accumulated API mass in the absorption chamber agreed well with the 89% reduction in mean Cmax and the 82% reduction in mean AUC from dog PK study between animals treated with pentagastrin and famotidine. Testing of the compound A optimized formulation tablets showed a 25% reduction in flux and in vitro absorbed amount by changing pH 1.6 to 4.0, correlating well with the AUC decrease in clinical studies. Good correlation between in vitro data and in vivo PK data demonstrated the applicability of the method for formulators to develop drug products mitigating DDI from ARAs.


pH gradient dissolution in-situ flux measurement acid reducing agents (ARAs) drug-drug interactions (DDIs) dosage form 



The authors would like to recognize contribution of Mr. Ram Lingamaneni of Pion Inc. (currently at Catalent) who helped collecting data presented in this paper. The authors would like to acknowledge Drs. Dawen Kou and Mark Ragains of Genentech for their input during the execution of the project, Dr. Gena Dalziel of Genentech for GDC-0941 discussions, and Dr. Lichuan Liu of Genentech for technical discussions on GDC-0810 during the manuscript preparation.


  1. 1.
    Elder DP. Effective formulation development strategies for poorly soluble active pharmaceutical ingredients (APIs). Am Pharm Rev. 2011;12(2):56–61.Google Scholar
  2. 2.
    Lignet F, Sherbetjian E, Kratochwil N, Jones R, Suenderhauf C, Otteneder MB, et al. Parrott N characterization of pharmacokinetics in the Gottingen minipig with reference human drugs: an in vitro and in vivo approach. Pharm Res. 2016;33:2565–79.CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang T, Heimbach T, Lin W, Zhang J, He HD. Prospective predictions of human pharmaceutics for eighteen compounds. J Pharm Sci. 2015;104:2795–806.CrossRefPubMedGoogle Scholar
  4. 4.
    Bhattachar SN, Perkins EJ, Tan JS, Burns LJ. Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus™ simulations to predict absorption. J Pharm Sci. 2011;100:4756–65.CrossRefPubMedGoogle Scholar
  5. 5.
    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
  6. 6.
    Lainé AL, Price D, Davis J, Roberts D, Hudson R, Back K, et al. Enhanced oral delivery of celecoxib via the development of a supersaturable amorphous formulation utilizing mesoporous silica and co-loaded HPMCAS. In J Pharm. 2016;512:118–25.Google Scholar
  7. 7.
    Van Speybroeck M, Mols R, Mellaerts Randy R, Thi TD, Martens JA, Van Humbeeck J, et al. Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral absorption of the poorly soluble weak base itraconazole. Eur J Pharm Biopharm. 2010;75:354–65.CrossRefPubMedGoogle Scholar
  8. 8.
    Lui CY, Amidon GL, Berardi RR, Fleisher D, Youngberg C, Dressman JB. Comparison of gastrointestinal pH in dogs and humans: implications on the use of the beagle dogs as a model for oral absorption in humans. J Pharm Sci. 1986;75:271–4.CrossRefPubMedGoogle Scholar
  9. 9.
    Pang J, Dalziel G, Dean B, Ware JA, Salphati L. Pharmacokinetics and absorption of the anticancer agents dasatinib and GDC-0941 under various gastric conditions in dogs—reversing the effect of elevated gastric pH with betaine HCl. Mol Pharm. 2013;10:4024–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Mitra A, Kesisoglou F, Beauchamp M, Zhu W, Chiti F, Wu Y. Using absorption simulation and gastric pH modulated dog model for formulation development to overcome achlorhydria effect. Mol Pharm. 2011;8:2216–23.CrossRefPubMedGoogle Scholar
  11. 11.
    Targownik LE, Metge C, Roos L, Leung S. The prevalence of and the clinical and demographic characteristics associated with high-intensity proton pump inhibitor use. Am J Gastroenterol. 2007;102:942–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Smelick GS, Heffron TO, Chu L, Dean B, West DA, DuVall SL, et al. Prevalence of acid-reducing agents (ARAs) in cancer patients and ARA drug-drug interaction potential for molecular targeted agents in clinical development. Mol Pharm. 2013;10:4055–62.CrossRefPubMedGoogle Scholar
  13. 13.
    Koneru B, Cowart DT, Noorisa M, Kisicki J, Bramer SL. Effect of increasing gastric pH with famotidine on absorption and oral pharmacokinetics of the inotropic agent vesnarinone. J Clin Pharmacol. 1998;38:429–32.CrossRefPubMedGoogle Scholar
  14. 14.
    Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, et al. Drug absorption interactions between oral targeted anticancer agents & PPIs: is pH-dependent solubility the achilles heel of targeted therapy? Clin Pharmacol Ther. 2012;92:203–13.CrossRefPubMedGoogle Scholar
  15. 15.
    Lahner E, Annibale B, Fave GD. Systemic review: impaired drug absorption related to the co-administration of antisecretory therapy. Aliment Pharmacol Ther. 2009;29:1219–29.CrossRefPubMedGoogle Scholar
  16. 16.
    Badawy SIF, Gray DB, Zhao F, Sun DX, Schuster AE, Hussain MA. Formulation of solid dosage forms to overcome gastric pH interaction of factor Xa inhibitor, BMS-561389. Pharm Res. 2006;23:989–96.CrossRefPubMedGoogle Scholar
  17. 17.
    Kostewicz ES, Abrahamsson B, Brewster M, Brouwers J, Butler J, Carlert C, et al. In vitro models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci. 2014;57:342–66.CrossRefPubMedGoogle Scholar
  18. 18.
    Klein S. The use of Biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J. 2010;12:397–406.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Klein S, Dressman JB. Comparison of drug release from metoprolol modified released forms in single buffer versus a pH-gradient dissolution test. Dissolution Technologies. 2006;13:6–11.Google Scholar
  20. 20.
    Mathias NR, Xu Y, Patel D, Grass M, Caldwell B, Jager C, et al. Assessing the risk of pH-dependent absorption for new molecular entities: a novel in vitro dissolution test, physicochemical analysis and risk assessment strategy. Mol Pharm. 2013;10:4063–73.CrossRefPubMedGoogle Scholar
  21. 21.
    Gao P, Shi Y. Characterization of supersaturatable formulations for improved absorption of poorly soluble drugs. AAPS J. 2012;14:703–13.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kou D, Dwaraknath S, Fischer Y, Nguyen D, Kim M, Yiu H, et al. Biorelevant dissolution models for a weak base to facilitate formulation development and overcome reduced bioavailability caused by hypochlorhydria or achlorhydria. Mol Pharm. 2017;10:3577–87.CrossRefGoogle Scholar
  23. 23.
    Pestieau A, Evrard B. In vitro biphasic dissolution tests and their suitability for establishing in vitro-in vivo correlations: a historical review. Eur J Pharm Sci. 2017;102:203–19.CrossRefPubMedGoogle Scholar
  24. 24.
    Xu H, Shi Y, Vela S, Marroum P, Gao P. Developing quantitative in vitro-in vivo correlation for fenofibrate immediate-release formulations with the biphasic dissolution–partition test method. J Pharm Sci. 2018;107:476–87.CrossRefPubMedGoogle Scholar
  25. 25.
    Heigoldt U, Sommer F, Daniels R, Wagner K-G. Predicting in vivo absorption behavior of oral modified release dosage forms containing pH-dependent poorly soluble drugs using a novel pH-adjusted biphasic in vitro dissolution test. Eur J Pharm Biopharm. 2010;75:105–11.CrossRefGoogle Scholar
  26. 26.
    Deng J, Staufenbiel S, Bodmeier R. Evaluating a biphasic in vitro dissolution test for estimating the bioavailability of carbamazepine polymorphic forms. Eur J Pharm Sci. 2017;105:64–70.CrossRefPubMedGoogle Scholar
  27. 27.
    Kataoka M, Masaoka Y, Sakuma S, Yamashita S. Effect of food intake on the oral absorption of poorly water-soluble drugs: in vitro assessment of drug dissolution and permeation assay system. J Pharm Sci. 2006;95(9):2051–61.CrossRefPubMedGoogle Scholar
  28. 28.
    Kataoka M, Fukahori M, Ikemura A, Kubota A, Higashino H, Sakuma S, et al. Effects of gastric pH on oral drug absorption: in vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process. Eur J Pharm Biopharm. 2016;101:103–11.CrossRefPubMedGoogle Scholar
  29. 29.
    Raina SA, Zhang GGZ, 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. 2014;103(9):2736–48.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhu A, Ho MC, Gemski CK, Chuang BC, Liao M, Xia C. Utilizing in vitro dissolution-permeation chamber for the quantitative predication of pH-dependent drug-drug interactions with acid-reducing agents: a comparison with physiologically based pharmacokinetic modeling. AAPS J. 2016;18:1512–23.CrossRefPubMedGoogle Scholar
  31. 31.
    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;41:1007–10.CrossRefPubMedGoogle Scholar
  32. 32.
    Avdeef A, Artursson P, Neuhoff S, Lazorova L, Grasjoe J, Tavelin S. Caco-2 permeability of weakly basic drugs predicted with the double-sink PAMPA pKfluxa method. Eur J Pharm Sci. 2005;24:333–49.CrossRefPubMedGoogle Scholar
  33. 33.
    Bermejo M, Avdeef A, Ruiz A, Nalda R, Ruell JA, Tsinman O, et al. PAMPA—a drug absorption in vitro model 7. Comparing rat in situ, Caco-2, and PAMPA permeability of fluoroquinolones. Eur J Pharm Sci. 2004;21:429–41.CrossRefPubMedGoogle Scholar
  34. 34.
    Forner K, Holm R, Morakul B, Junyaprasert VB, Ackermann M, Mazur J, et al. Dissolution and dissolution/permeation experiments for predicting systemic exposure following oral administration of the BCS class II drug clarithromycin. Eur J Pharm Sci. 2017;101:211–9.CrossRefGoogle Scholar
  35. 35.
    Borbás E, Nagy ZK, Nagy B, Balogh A, Farkas B, Tsinman O, et al. The effect of formulation additives on in vitro dissolution-absorption profile and in vivo bioavailability of telmisartan from brand and generic formulations. Eur J Pharm Sci. 2018;114(January):310–7. Available from: CrossRefPubMedGoogle Scholar
  36. 36.
    Hou HH, Jia W, Liu L, Cheeti S, Li J, Nauka E, et al. Effect of microenvironmental pH modulation on the dissolution rate and oral absorption of the salt of a weak acid—case study of GDC-0810. Pharm Res. 2018;35(2):37. Scholar
  37. 37.
    Avdeef A, Bendels S, Tsinman O, Tsinman K, Kansy M. Solubility-excipient classification gradient maps. Pharm Res. 2007;24(3):530–45.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Jane Li
    • 1
  • Konstantin Tsinman
    • 2
    Email author
  • Oksana Tsinman
    • 2
  • Larry Wigman
    • 1
  1. 1.GenentechSouth San FranciscoUSA
  2. 2.Pion Inc.BillericaUSA

Personalised recommendations