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Evaluating Oral Drug Delivery Systems: Dissolution Models

  • Ragna BerthelsenEmail author
  • Anette Müllertz
  • Thomas Rades
Chapter
Part of the Advances in Delivery Science and Technology book series (ADST)

Abstract

For the past decades a range of dissolution models has been developed and routineously used to evaluate drug release from semisolid and solid oral dosage forms. Their use has been for both research and development, and quality control (QC) purposes. It is thus not surprising that the different dissolution models span a large range in terms of complexity; from simple systems like the pharmacopoeial QC tests to more complex systems like the transfer model and the biphasic dissolution model. In this chapter the basic principle of the dissolution process for orally administrated drugs is described alongside a series of different dissolution models including pharmacopoeial models, dissolution models utilising physiologically relevant dissolution media, small volume and biphasic dissolution models, transfer models and combined dissolution-permeation models. All models are evaluated in terms of their common use and limitations.

Keywords

Biphasic dissolution Combined dissolution-absorption models Dissolution GI tract In vitro Pharmacopoeial models Physiologically relevant media Poorly water soluble drugs Transfer models 

References

  1. Aulton M (2013) Properties of solutions. In: Aulton M, Taylor KMG (eds) Aulton’s pharmaceutics: the design and manufacture of medicines. Elsevier, Edinburgh, pp 38–48Google Scholar
  2. Azarmi S, Roa W, Lobenberg R (2007) Current perspectives in dissolution testing of conventional and novel dosage forms. Int J Pharm 328:12–21CrossRefPubMedGoogle Scholar
  3. Bai G, Armenante PM, Plank RV, Gentzler M, Ford K, Harmon P (2007) Hydrodynamic investigation of USP dissolution test apparatus II. J Pharm Sci 96:2327–2349CrossRefPubMedGoogle Scholar
  4. Bakatselou V, Oppenheim RC, Dressman JB (1991) Solubilization and wetting effects of bile salts on the dissolution of steroids. Pharm Res 8:1461–1469CrossRefPubMedGoogle Scholar
  5. Bates TR, Gibaldi M, Kanig JL (1966a) Solubilizing properties of bile salt solutions. I. Effect of temperature and bile salt concentration on solubilization of glutethimide, griseofulvin, and hexestrol. J Pharm Sci 55:191–199CrossRefPubMedGoogle Scholar
  6. Bates TR, Gibaldi M, Kanig JL (1966b) Solubilizing properties of bile salt solutions. II. Effect of inorganic electrolyte, lipids, and a mixed bile salt system on solubilization of glutethimide, griseofulvin, and hexestrol. J Pharm Sci 55:901–906CrossRefPubMedGoogle Scholar
  7. Baxter JL, Kukura J, Muzzio FJ (2005) Hydrodynamics-induced variability in the USP apparatus II dissolution test. Int J Pharm 292:17–28CrossRefPubMedGoogle Scholar
  8. Bergstrom CA, Holm R, Jorgensen SA, Andersson SB, Artursson P, Beato S, Borde A, Box K, Brewster M, Dressman J, Feng KI, Halbert G, Kostewicz E, McAllister M, Muenster U, Thinnes J, Taylor R, Mullertz A (2014) Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs. Eur J Pharm Sci 57:173–199CrossRefPubMedGoogle Scholar
  9. Berthelsen R, Sjogren E, Jacobsen J, Kristensen J, Holm R, Abrahamsson B, Mullertz A (2014) Combining in vitro and in silico methods for better prediction of surfactant effects on the absorption of poorly water soluble drugs—A fenofibrate case example. Int J Pharm 473:356–365CrossRefPubMedGoogle Scholar
  10. Bevernage J, Brouwers J, Clarysse S, Vertzoni M, Tack J, Annaert P, Augustijns P (2010) Drug supersaturation in simulated and human intestinal fluids representing different nutritional states. J Pharm Sci 99:4525–4534CrossRefPubMedGoogle Scholar
  11. Bevernage J, Brouwers J, Brewster ME, Augustijns P (2013) Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues. Int J Pharm 453:25–35CrossRefPubMedGoogle Scholar
  12. Buch P, Langguth P, Kataoka M, Yamashita S (2009) IVIVC in oral absorption for fenofibrate immediate release tablets using a dissolution/permeation system. J Pharm Sci 98:2001–2009CrossRefPubMedGoogle Scholar
  13. Carlert S, Palsson A, Hanisch G, von Corswant C, Nilsson C, Lindfors L, Lennernas H, Abrahamsson B (2010) Predicting intestinal precipitation—a case example for a basic BCS class II drug. Pharm Res 27:2119–2130CrossRefPubMedGoogle Scholar
  14. Constantinides PP, Wasan KM (2007) Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: In vitro/in vivo case studies. J Pharm Sci 96:235–248CrossRefPubMedGoogle Scholar
  15. de Campos DR, Klein S, Zoller T, Vieria NR, Barros FA, Meurer EC, Coelho EC, Marchioretto MA, Pedrazzoli J (2010) Evaluation of pantoprazole formulations in different dissolution apparatus using biorelevant medium. Arzneimittelforschung 60:42–47PubMedGoogle Scholar
  16. Dressman JB, Amidon GL, Reppas C, Shah VP (1998) Dissolution testing as a prognostic tool for oral drug absorption: Immediate release dosage forms. Pharm Res 15:11–22CrossRefPubMedGoogle Scholar
  17. Ehrhardt M, Lindenmaier H, Burhenne J, Haefeli WE, Weiss J (2004) Influence of lipid lowering fibrates on P-glycoprotein activity in vitro. Biochem Pharmacol 67:285–292CrossRefPubMedGoogle Scholar
  18. FDA (1997) Guidance for industry: Dissolution testing of immediate release solid oral dosage forms. Center for Drug Evaluation and Research (CDER), U.S. Department of Health and Human Services, Food and Drug Administration, Silver Spring, August 1997Google Scholar
  19. Fotaki N (2011) Flow-through cell apparatus (USP apparatus 4): Operation and features. Dissolution Technol 18:46–49CrossRefGoogle Scholar
  20. Galia E, Nicolaides E, Horter D, Lobenberg R, Reppas C, Dressman JB (1998) Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res 15:698–705CrossRefPubMedGoogle Scholar
  21. Ginski MJ, Polli JE (1999) Prediction of dissolution-absorption relationships from a dissolution/Caco-2 system. Int J Pharm 177:117–125CrossRefPubMedGoogle Scholar
  22. Ginski MJ, Taneja R, Polli JE (1999) Prediction of dissolution-absorption relationships from a continuous dissolution/Caco-2 system. AAPS PharmSci 1, E3CrossRefPubMedGoogle Scholar
  23. Heigoldt U, Sommer F, Daniels R, Wagner KG (2010) 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 76:105–111CrossRefPubMedGoogle Scholar
  24. Helander HF, Fandriks L (2014) Surface area of the digestive tract—Revisited. Scand J Gastroenterol 49:681–689CrossRefPubMedGoogle Scholar
  25. Hidalgo IJ, Raub TJ, Borchardt RT (1989) Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96:736–749CrossRefPubMedGoogle Scholar
  26. Horn D, Rieger J (2001) Organic nanoparticles in the aqueous phase—Theory, experiment, and use. Angew Chem Int Ed 40:4331–4361CrossRefGoogle Scholar
  27. Ingels F, Deferme S, Destexhe E, Oth M, Van den Mooter G, Augustijns P (2002) Simulated intestinal fluid as transport medium in the Caco-2 cell culture model. Int J Pharm 232:183–192CrossRefPubMedGoogle Scholar
  28. Jantratid E, Janssen N, Chokshi H, Tang K, Dressman JB (2008a) Designing biorelevant dissolution tests for lipid formulations: Case example–lipid suspension of RZ-50. Eur J Pharm Biopharm 69:776–785CrossRefPubMedGoogle Scholar
  29. Jantratid E, Janssen N, Reppas C, Dressman JB (2008b) Dissolution media simulating conditions in the proximal human gastrointestinal tract: An update. Pharm Res 25:1663–1676CrossRefPubMedGoogle Scholar
  30. Jantratid E, De Maio V, Ronda E, Mattavelli V, Vertzoni M, Dressman JB (2009) Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form. Eur J Pharm Sci 37:434–441CrossRefPubMedGoogle Scholar
  31. Kataoka M, Masaoka Y, Yamazaki Y, Sakane T, Sezaki H, Yamashita S (2003) In vitro system to evaluate oral absorption of poorly water-soluble drugs: Simultaneous analysis on dissolution and permeation of drugs. Pharm Res 20:1674–1680CrossRefPubMedGoogle Scholar
  32. Kleberg K, Jacobsen J, Mullertz A (2010) Characterising the behavior of poorly water soluble drugs in the intestine: Application of biorelevant media for solubility, dissolution and transport studies. J Pharm Pharmacol 62:1–13CrossRefGoogle Scholar
  33. Klein S, Shah VP (2008) A standardized mini paddle apparatus as an alternative to the standard paddle. AAPS PharmSciTech 9:1179–1184CrossRefPubMedPubMedCentralGoogle Scholar
  34. Klein S, Buchanan NL, Buchanan CM (2012) Miniaturized transfer models to predict the precipitation of poorly soluble weak bases upon entry into the small intestine. AAPS PharmSciTech 13:1230–1235CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kobayashi M, Sada N, Sugawara M, Iseki K, Miyazaki K (2001) Development of a new system for prediction of drug absorption that takes into account drug dissolution and pH change in the gastro-intestinal tract. Int J Pharm 221:87–94CrossRefPubMedGoogle Scholar
  36. Kostewicz ES, Wunderlich M, Brauns U, Becker R, Bock T, Dressman JB (2004) Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine. J Pharm Pharmacol 56:43–51CrossRefPubMedGoogle Scholar
  37. Kostewicz ES, Abrahamsson B, Brewster M, Brouwers J, Butler J, Carlert S, Dickinson PA, Dressman J, Holm R, Klein S, Mann J, McAllister M, Minekus M, Muenster U, Mullertz A, Verwei M, Vertzoni M, Weitschies W, Augustijns P (2014) In vitro models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci 57C:342–366CrossRefGoogle Scholar
  38. Lennernäs H, Palm K, Fagerholm U, Artursson P (1996) Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo. Int J Pharm 127:103–107CrossRefGoogle Scholar
  39. Li J, Yang L, Ferguson SM, Hudson TJ, Watanabe S, Katsuma M, Fix JA (2002) In vitro evaluation of dissolution behavior for a colon-specific drug delivery system (CODES) in multi-pH media using United States Pharmacopeia apaaratus II nad III. AAPS PharmSciTech 3:1–9CrossRefGoogle Scholar
  40. Lobenberg R, Kramer J, Shah VP, Amidon GL, Dressman JB (2000) Dissolution testing as a prognostic tool for oral drug absorption: Dissolution behavior of glibenclamide. Pharm Res 17:439–444CrossRefPubMedGoogle Scholar
  41. Lue BM, Nielsen FS, Magnussen T, Schou HM, Kristensen K, Jacobsen LO, Mullertz A (2008) Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound. Eur J Pharm Biopharm 69:648–657CrossRefPubMedGoogle Scholar
  42. Motz SA, Schaefer UF, Balbach S, Eichinger T, Lehr CM (2007) Permeability assessment for solid oral drug formulations based on Caco-2 monolayer in combination with a flow through dissolution cell. Eur J Pharm Biopharm 66:286–295CrossRefPubMedGoogle Scholar
  43. Mudie DM, Amidon GL, Amidon GE (2010) Physiological parameters for oral delivery and in vitro testing. Mol Pharm 7:1388–1405CrossRefPubMedPubMedCentralGoogle Scholar
  44. Mudie DM, Murray K, Hoad CL, Pritchard SE, Garnett MC, Amidon GL, Gowland PA, Spiller RC, Amidon GE, Marciani L (2014) Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state. Mol Pharm 11:3039–3047CrossRefPubMedGoogle Scholar
  45. Nernst W, Brunner E (1904) Theorie der Reaktionsgeschwimdigkeit in heterogenen Systemen. Zeitschrift f Physik Chemie 47:52–110Google Scholar
  46. Nicolaides E, Galia E, Efthymiopoulos C, Dressman JB, Reppas C (1999) Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data. Pharm Res 16:1876–1882CrossRefPubMedGoogle Scholar
  47. Niebergall P, Patil MY, Sugita ET (1967) Simultaneous determination of dissolution and partitioning rates in vitro. J Pharm Sci 56:943–947. doi: 10.1002/jps.2600560803 CrossRefPubMedGoogle Scholar
  48. Noyes AA, Whitney WR (1897) The rate of solution of solid substance in their own solutions. J Am Chem Soc 19:930–934CrossRefGoogle Scholar
  49. Perng CY, Kearney AS, Palepu NR, Smith BR, Azzarano LM (2003) Assessment of oral bioavailability enhancing approaches for SB-247083 using flow-through cell dissolution testing as one of the screens. Int J Pharm 250:147–156CrossRefPubMedGoogle Scholar
  50. Phillips DJ, Pygall SR, Cooper VB, Mann JC (2012) Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems. J Pharm Pharmacol 64:1549–1559CrossRefPubMedGoogle Scholar
  51. Psachoulias D, Vertzoni M, Butler J, Busby D, Symillides M, Dressman J, Reppas C (2012) An in vitro methodology for forecasting luminal concentrations and precipitation of highly permeable lipophilic weak bases in the fasted upper small intestine. Pharm Res 29:3486–3498CrossRefPubMedGoogle Scholar
  52. Qureshi SA, Caill’e G, Brien R, Piccirilli G, Yu V, McGilvaray IJ (1994) Application of flow-through dissolution method for the evaluation of oral formulations of nifedipine. Drug Dev Ind Pharm 20:1869–1882CrossRefGoogle Scholar
  53. Sawada GA, Ho NF, Williams LR, Barsuhn CL, Raub TJ (1994) Transcellular permeability of chlorpromazine demonstrating the roles of protein binding and membrane partitioning. Pharm Res 11:665–673CrossRefPubMedGoogle Scholar
  54. Schiller C, Frohlich CP, Giessmann T, Siegmund W, Monnikes H, Hosten N, Weitschies W (2005) Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment Pharmacol Ther 22:971–979CrossRefPubMedGoogle Scholar
  55. Scholz A, Kostewicz E, Abrahamsson B, Dressman JB (2003) Can the USP paddle method be used to represent in-vivo hydrodynamics? J Pharm Pharmacol 55:443–451CrossRefPubMedGoogle Scholar
  56. Sheng JJ, Kasim NA, Chandrasekharan R, Amidon GL (2006) Solubilization and dissolution of insoluble weak acid, ketoprofen: Effects of pH combined with surfactant. Eur J Pharm Sci 29:306–314CrossRefPubMedGoogle Scholar
  57. Shi Y, Gao P, Gong YC, Ping HL (2010) 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 7:1458–1465CrossRefPubMedGoogle Scholar
  58. Sugawara M, Kadomura S, He X, Takekuma Y, Kohri N, Miyazaki K (2005) The use of an in vitro dissolution and absorption system to evaluate oral absorption of two weak bases in pH-independent controlled-release formulations. Eur J Pharm Sci 26:1–8CrossRefPubMedGoogle Scholar
  59. Sunesen VH, Pedersen BL, Kristensen HG, Mullertz A (2005) In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media. Eur J Pharm Sci 24:305–313CrossRefPubMedGoogle Scholar
  60. The European Directorate for the Quality of Medicines and HealthCare (2014a) European Pharmacopoeia Online 8.2. 5.17.1. Recommendations on dissolution testing, 10 June 2014Google Scholar
  61. The European Directorate for the Quality of Medicines and HealthCare (2014b) European Pharmacopoeia Online 8.2. 2.9.3. Dissolution test for dolid dosage forms, June 10 2014Google Scholar
  62. The United States Pharmacopeia and National Formulary (2011) USP 34 - NF 29. Official Monographs/FenofibrateGoogle Scholar
  63. The United States Pharmacopeia and National Formulary (2014a) USP 37 - NF 32. <1092> The dissolution procedure: Development and validation, June 10 2014Google Scholar
  64. The United States Pharmacopeia and National Formulary (2014b) USP 37 - NF 32. <711> Dissolution, June 10 2014Google Scholar
  65. Thybo P, Pedersen BL, Hovgaard L, Holm R, Mullertz A (2008) Characterization and physical stability of spray dried solid dispersions of probucol and PVP-K30. Pharm Dev Technol 13:375–386CrossRefPubMedGoogle Scholar
  66. Vertzoni M, Fotaki N, Kostewicz E, Stippler E, Leuner C, Nicolaides E, Dressman J, Reppas C (2004) Dissolution media simulating the intraluminal composition of the small intestine: Physiological issues and practical aspects. J Pharm Pharmacol 56:453–462CrossRefPubMedGoogle Scholar
  67. Vertzoni M, Dressman J, Butler J, Hempenstall J, Reppas C (2005) Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds. Eur J Pharm Biopharm 60:413–417CrossRefPubMedGoogle Scholar

Copyright information

© Controlled Release Society 2016

Authors and Affiliations

  • Ragna Berthelsen
    • 1
    Email author
  • Anette Müllertz
    • 2
  • Thomas Rades
    • 1
  1. 1.Department of PharmacyUniversity of CopenhagenCopenhagenDenmark
  2. 2.Bioneer:FARMA, Department of PharmacyUniversity of CopenhagenCopenhagenDenmark

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