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Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms

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Abstract

Dissolution tests are used for many purposes in the pharmaceutical industry: in the development of new products, for quality control and, to assist with the determination of bioequivalence. Recent regulatory developments such as the Biopharmaceutics Classification Scheme have highlighted the importance of dissolution in the regulation of post-approval changes and introduced the possibility of substituting dissolution tests for clinical studies in some cases. Therefore, there is a need to develop dissolution tests that better predict the in vivo performance of drug products. This could be achieved if the conditions in the gastrointestinal tract were successfully reconstructed in vitro. The aims of this article are, first, to clarify under which circumstances dissolution testing can be prognostic for in vivo performance, and second, to present physiological data relevant to the design of dissolution tests, particularly with respect to the composition, volume, flow rates and mixing patterns of the fluids in the gastrointestinal tract. Finally, brief comments are made in regard to the composition of in vitro dissolution media as well as the hydrodynamics and duration of the test.

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REFERENCES

  1. The United States Pharmacopeia (USP 23). United States Pharmacopeial Convention, Inc., Rockville, MD (1995).

  2. Guidance for Industry, Immediate Release Solid oral Dosage Forms, Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation, CDER, Food and Drug Administration, USA, 1995.

  3. Dissolution Testing of Solid Oral Products: Joint Report of the Section for Official Laboratories and Medicines Control Services and the Section of Industrial Pharmacists of the FIP, Dissolution Tech. 4:5–14 (1997).

  4. P. Macheras, C. Reppas, and J. B. Dressman. Biopharmaceutics of Orally Administered Dosage Forms. Ellis Horwood Ltd., Series in Pharmaceutical Technology, Chichester, ISBN 0-13-108093-8, UK, 1995.

    Google Scholar 

  5. G. L. Amidon, H. Lennernås, V. P. Shah, and J. R. A. Crison. Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm. Res. 12:413–420 (1995).

    Google Scholar 

  6. H. Lennernås, Ö. Ahrenstedt, R. Hällgren, L. Knutson, M. Ryde, and L. K. Paalzow. Regional Jejunal Perfusion, a New In Vivo Approach to Study Oral Drug Absorption in Man. Pharm. Res. 9:1243–51 (1992).

    Google Scholar 

  7. T. Gramatte. Die Lokalisationsabhängigkeit der Arzneistoffresorption im Dünndarm des Menschen. Shaker Verlag, Aachen, ISBN 3-8265-1435-1, Germany, 1996.

    Google Scholar 

  8. J. B. Dressman and D. Fleisher. Mixing-tank Model for Predicting Dissolution Rate Control of Oral Absorption. J. Pharm. Sci. 75:109–116 (1986).

    Google Scholar 

  9. H. W. Davenport. Intestinal Absorption of Water and Electrolytes, in: Physiology of the Gastrointestinal Tract. 5th. Edition, Chapter 13, Year Book Medical Publishers, Chicago ISBN 0-8151-2330-2, USA, 1982.

    Google Scholar 

  10. W. Nernst and E. Brunner. Theorie der Reaktionsgeschwindigkeit in Heterogenen Systemen. Z. Physik. Chem. 47:52–110 (1904).

    Google Scholar 

  11. V. G. Levich. Physicochemical Hydrodynamics, Englewood Cliffs, Prentice Hall, New Jersey, 1962.

    Google Scholar 

  12. A. S. Noyes and W. R. Whitney. The Rate of Solution of Solid Substances in Their Own Solutions. J. Am. Chem. Soc. 19:930–934 (1897).

    Google Scholar 

  13. J. B. Dressman, R. R. Berardi, L. C. Dermentzoglou, T. L. Russell, S. P. Schmaltz, J. L. Barnett, and K. Jarvenpaa. Upper Gastrointestinal pH in Young, Healthy Men and Women. Pharm. Res. 7:756–761 (1990).

    Google Scholar 

  14. T. L. Russell, R.R. Berardi, J. L. Barnett, L. C. Dermentzoglou, K. M. Jarvenpaa, S. P. Schmaltz, and J. B. Dressman. Upper Gastrointestinal pH in Seventy-nine Healthy, Elderly North American Men and Women. Pharm. Res. 10:187–196 (1993).

    Google Scholar 

  15. P. Christiansen. The Incidence of Achlorhydria in Healthy Subjects and Patients with Gastrointestinal Diseases. Scand. J. Gastroenterology 3:497–508 (1968).

    Google Scholar 

  16. H. Ogata, N. Aoyagi, A. Kaniwa, A. Ejima, K. Suzuki, T. Ishioka, M. Morishita, K. Ohta, Y. Takagishi, Y. Doi, and T. Ogura. Development and Evaluation of a New Peroral Test Agent GA-Test for Assessment of Gastric Acidity. J. Pharmacobio-Dyn. 7:656–664 (1984).

    Google Scholar 

  17. V. Gray and J. B. Dressman. Simulated Intestinal Fluid, TS-Change to pH 6.8. Pharmacopeial Forum 22: 1943–1945 (1996).

    Google Scholar 

  18. J. H. Cummings, E. W. Pomare, W. J. Branch, C. P. E. Naylor, and G. T. MacFarlane. Short Chain Fatty Acids in Human Large Intestine, Portal, Hepatic and Venous Blood. Gut 28: 1221–1227 (1987).

    Google Scholar 

  19. S. S. Ozturk, B. O. Palsson, and J. B. Dressman. Dissolution of Ionizable Drugs in Buffered and Unbuffered Solutions. Pharm. Res. 5:550–565 (1988).

    Google Scholar 

  20. D. G. Greenwood, Small Intestinal pH and Buffer Capacity: Implications for Dissolution of Ionizable Compounds, Doctoral Thesis, University of Michigan, Ann Arbor, Michigan, USA, 1994.

    Google Scholar 

  21. P. Finholt and S. Solvang. Dissolution Kinetics of Drugs in Human Gastric Juice: The Role of Surface Tension. J. Pharm. Sci. 57:1322–1326 (1968).

    Google Scholar 

  22. G. P. van Berge Henegouwen and A. F. Hofmann. Nocturnal Gallbladder Storage and Emptying in Gallstone Patients and Healthy Subjects. Gastroenterology, 75: 879–885 (1978).

    Google Scholar 

  23. A. Tangerman, A. van Schaik, and E. W. van der Hoek. Analysis of Conjugated and Unconjugated Bile Acids in Serum and Jejunal Fluid of Normal Subjects. Clin. Chim. Acta 159:123–132 (1986).

    Google Scholar 

  24. T. L. Peeters, G. Vantrappen, and J. Janssens. Bile Acid Output and the Interdigestive Micgrating Motor Complex in Normals and in Cholecystectomy patients. Gastroenterology 79:678–681 (1980).

    Google Scholar 

  25. L. Marzio, M. Neri, F. Capone, F. Di Felice, C. De Angelis, A. Mezzeti, and F. Cuccurullo. Gallbladder Contraction and Its Relationship to Interdigestive Duodenal Motor Activity in Normal Human Subjects. Dig. Dis. Sci. 33:540–544 (1988).

    Google Scholar 

  26. H. W. Davenport. Secretion of the Bile, in: Physiology of the Gastrointestinal Tract, 5th. Edition, Chapter 11, Year Book Medical Publishers, Chicago, ISBN 0-8151-2330-2, USA, 1982.

    Google Scholar 

  27. B. Borgstrom, A. Dahlqvist, G. Lundh, and J. Sjovall. Studies of Intestinal Digestion and Absorption in the Human. J. Clin. Invest. 36:1521–1536 (1957).

    Google Scholar 

  28. J. Sjovall. On the Concentrations of Bile Acids in the Human Intestine During Absorption. Acta Physiol. Scand. 46:339–345 (1959).

    Google Scholar 

  29. O. Fausa. Duodenal Bile Acids After a Test Meal. Scand. J. Gastroenterol. 9:567–570 (1974).

    Google Scholar 

  30. M. Rautureau, A. Bissali, and J.-C. Rambaud. Bile Salts and Lipids in Aqueous Intraluminal Phase During the Digestion of a Standard Meal in a Normal Man. Gastroenterol. Clin. Biol. 5:417–425 (1981).

    Google Scholar 

  31. T. E. Solomon. Exocrine Pancreas: Pancreatitis, Unit 16 in: Undergraduate Teaching Series (American Gastroenterological Association), Milner-Fenwick Inc., Maryland, 1984, USA.

    Google Scholar 

  32. A. S. Uch and J. B. Dressman. Improving Bioavailability by Colonic Administration, in: Formulation of Poorly-Available Drugs for Oral Administration (Minutes of the European Symposium), Editions de Sante, Paris, ISBN 2-86411-096-2, 1996.

  33. H. Bronsted and J. Kopecek. Hydrogels for site-specific drug delivery to the colon: in vitro and in vivo degradation. Pharm. Res. 9:1540–1545 (1992).

    Google Scholar 

  34. J. Kopecek, P. Kopeckova, H. Bronsted, R. Rathi, B. Rihova, P.-Y. Yeh, and K. Ikesue. Polymers for colon-specific drug delivery. J. Controlled Release 19:121–130 (1992).

    Google Scholar 

  35. G. Van de Mooter, C. Samyn, and R. Kinget. Azo Polymers for colon-specific drug delivery. Int. J. Pharm. 87:37–46 (1992).

    Google Scholar 

  36. H. W. Davenport. Gastric Motility and Emptying, in: Physiology of the Gastrointestinal Tract, 5th. Edition, Chapter 4, Year Book Medical Publishers, Chicago, ISBN 0-8151-2330-2, USA, 1982.

    Google Scholar 

  37. K. Diem and C. Lentner. Documentia Geigy: Scientific Tables, Geigy Pharmaceuticals, Seventh Edition p. 651, Ardsley, New York, 1970.

  38. R. L. Dillard, H. Eastman, and J. S. Fordtran. Volume-Flow Relationship During the Transport of Fluid Through the Human Small Intestine. Gastroenterology 49:58–66 (1965).

    Google Scholar 

  39. J. S. Fordtran and T. Locklear. Ionic Constituents and Osmolarity of Gastric and Small Intestinal Fluids After Eating. Am. J. Dig. Dis. 11:503–521 (1966).

    Google Scholar 

  40. D. W. Powell. Intestinal Water and Electrolyte Transport, in: Physiology of the Gastrointestinal Tract, 2nd. Edition, Chapter 46, Ed. LR Johnson, Raven Press, New York, 0-88167-282-3, USA, 1987.

    Google Scholar 

  41. T. R. Hendrix, D. O. Castell, and J. D. Wood. Alimentary Tract Motility; Stomach, Small Intestine, Colon and Biliary Tract, Unit 10B in: Undergraduate Teaching Series (American Gastroenterological Association), Milner-Fenwick Inc., Maryland, 1987, USA.

    Google Scholar 

  42. M. G. Sarr, K. A. Kelly, and S. F. Phillips. Canine Jejunal Absorption and Transit During Interdigestive and Digestive Motor States. Am. J. Physiol. 239:G167–G172 (1980).

    Google Scholar 

  43. H. S. Wiggins and J. H. Cummings. Evidence for the Mixing of Residue in the Human Gut. Gut 17:1007–1011 (1976).

    Google Scholar 

  44. W. Brener, T. R. Hendrix, and P. R. McHugh. Regulation of the Gastric Emptying of Glucose. Gastroenterology 85:76–82 (1983).

    Google Scholar 

  45. R. L. Oberle, T.-S. Chen, C. Lloyd, J. L. Barnett, C. Owyang, J. Meyer, and G. L. Amidon. The Influence of the Interdigestive Migrating Myoelectric Complex on the Gastric Emptying of Liquids. Gastroenterology 99:1275–1282 (1990).

    Google Scholar 

  46. P. Kerlin, A. Zinsmeister, and S. Phillips. Relationship of Motility to Flow of Contents in the Human Small Intestine. Gastroenterology 83:701–706 (1982).

    Google Scholar 

  47. F. Hoelzel. The Rate of Passage of Inert Materials Through the Gastrointestinal Tract. Am. J. Physiol. 92:466–497 (1930).

    Google Scholar 

  48. V. A. John, P. A. Shotton, J. Moppert, and W. Theobold. Gastrointestinal Transit of Oros® Drug Delivery Systems in Healthy Volunteers: A Short Report. Br. J. Clin. Pharmacol. 19:203S–206S (1985).

    Google Scholar 

  49. P. J. Howard and R. C. Heading. The Role of Oesophageal Transit in Relation to Drug Delivery, in: Drug Delivery to the Gastrointestinal Tract, Hardy JG, Davis SS, Wilson CG (Editors), Chapter 2, Ellis Horwood, Chichester, ISBN 0-7458-0656-2, UK, 1989.

    Google Scholar 

  50. E. Hunter, J. T. Fell, and H. Sharma. The Gastric Emptying of Pellets Contained in Hard Gelatin Capsules. Drug Dev. Ind. Pharm. 8:751–757 (1982).

    Google Scholar 

  51. U. E. Jonsson, M. Alpsten, C. Bogentoft, R. Eriksson, and J. Sjögren. Gastric Emptying of Pellets and Tablets in Healthy Subjects Under Fasting and Nonfasting Conditions. 10th International Symposium on the Controlled Release of Bioactive Materials (CRS), p. 241 (1983).

  52. J. H. Meyer, J. Elashoff, V. Porter-Fink, J. Dressman, and G. L. Amidon. Human Postprandial Gastric Emptying of 1–3 Millimeter Spheres. Gastroenterology 94:1315–1325 (1988).

    Google Scholar 

  53. R. A. Hinder and K. A. Kelly. Canine Gastric Emptying of Solids and Liquids. Am. J. Physiol. 233:E335–E340 (1977).

    Google Scholar 

  54. M. C. Theodorakis, G. A. Digenis, R. M. Beihn, M. B. Shambhu, and F. H. DeLand. Rate and Pattern of Gastric Emptying in Humans Using 99mTc-Labeled Triethylenetetraamine-Polystyrene Resin. J. Pharm. Sci. 69:568–571 (1980).

    Google Scholar 

  55. R. K. Blythe, G. M. Grass, and D. R. MacDonnell. The Formulation and Evaluation of Enteric Coated Aspirin Tablets. Am. J. Pharm. pp. 206–216 (1959).

  56. J. G. Moore, P. E. Christian, and R. E. Coleman. Gastric Emptying of Varying Meal Weight and Composition in Man. Evaluation by Dual Liquid-and Solid-Phase Isotopic Method. Dig. Dis. Sci. 26:16–22 (1981).

    Google Scholar 

  57. S. S. Davis, J. G. Hardy, M. J. Taylor, D. R. Whalley, and C. G. Wilson. A Comparative Study of the Gastrointestinal Transit of a Pellet and Tablet Formulation. Int. J. Pharm. 21:167–177 (1984).

    Google Scholar 

  58. J.-R. Malagelada, J. S. Robertson, M. L. Brown, M. Remington, J. A. Duenes, G. M. Thomforde, and P. W. Carryer. Intestinal Transit of Solid and Liquid Components of a Meal in Health. Gastroenterology 87:1255–1263 (1984).

    Google Scholar 

  59. S. S. Davis, J. G. Hardy, and J. W. Fara. Transit of Pharmaceutical Dosage Forms Through the Small Intestine. Gut 27:886–892 (1986).

    Google Scholar 

  60. C. G. Wilson and N. Washington. Physiological Pharmaceutics-BiologicalBbarriers to Drug Absorption, Chapter 6, Ellis Horwood Series in Pharmaceutical Technology, Chichester, ISBN 0-7458-0543-4, UK, 1989.

  61. C. G. Wilson. Physiology of the GI Tract-Issues for the Absorption of Poorly-Soluble Drugs, in: Formulation of Poorly-Available Drugs for Oral Administration (Minutes of the European Symposium), Editions de Sante, Paris, ISBN 2-866411-096-2, France, 1996.

  62. M. Efentakis and J. B. Dressman. Gastric Juice as a Dissolution Medium: Surface Tension and pH. Eur. J. Drug Metab. Pharmacokin, (in press).

  63. P. Macheras, M. Koupparis, and E. Apostelelli. Dissolution of Four Controlled-Release Theophylline Formulations in Milk. Int. J. Pharm. 36:73–79 (in press).

  64. L. J. Ashby, A. E. Beezer, and G. Buckton. In Vitro Dissolution Testing of Oral Controlled Release Preparations in the Presence of Artificial Foodstuffs. I. Exploration of Alternative Methodology: Microcalorimetry. Int. J. Pharm. 51:245–251 (1989).

    Google Scholar 

  65. S. D. Mithani, V. Bakatselou, C. N. TenHoor, and J. B. Dressman. Estimation of the Increase in Solubility of Drugs as a Function of Bile Salt Concentration. Pharm. Res. 13:163–167 (1996).

    Google Scholar 

  66. C. M. O'Driscoll. Micellar Solubilization (Self-emulsifying Systems for Improved Absorption of Drugs), in: Formulation of Poorly-Available Drugs for Oral Administration (Minutes of the European Symposium), Editions de Sante, Paris, ISBN 2-866411-096-2, France, 1996.

  67. N. Katori, N. Aoyagi, and T. Terao. Estimation of Agitation Intensity in the Gi Tract in Humans and Dogs Based on In Vitro-In Vivo Correlation. Pharm. Res. 12:237–243 (1995).

    Google Scholar 

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Authors and Affiliations

  1. Institut für Pharmazeutische Technologie, Johann Wolfgang Goethe-Universität, Marie-Curie-Str. 9, 60439, Frankfurt am Main, Germany

    Jennifer B. Dressman

  2. College of Pharmacy, The University of Michigan, Ann Arbor, Michigan, 48109-1065

    Gordon L. Amidon

  3. Department of Pharmacy, University of Athens, Panepistimiopolis, 157 71, Zografou, Greece

    Christos Reppas

  4. Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, HFD-350, Rockville, Maryland, 20857

    Vinod P. Shah

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  1. Jennifer B. Dressman
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Dressman, J.B., Amidon, G.L., Reppas, C. et al. Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms. Pharm Res 15, 11–22 (1998). https://doi.org/10.1023/A:1011984216775

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