title: Physiological parameters for oral delivery and in vitro testing.
abstract: Pharmaceutical solid oral dosage forms must undergo dissolution in the intestinal fluids of the gastrointestinal tract before they can be absorbed and reach the systemic circulation. Therefore, dissolution is a critical part of the drug-delivery process. The rate and extent of drug dissolution and absorption depend on the characteristics of the active ingredient as well as properties of the dosage form. Just as importantly, characteristics of the physiological environment such as buffer species, pH, bile salts, gastric emptying rate, intestinal motility, and hydrodynamics can significantly impact dissolution and absorption. While significant progress has been made since 1970 when the first compendial dissolution test was introduced (USP apparatus 1), current dissolution testing does not take full advantage of the extensive physiologic information that is available. For quality control purposes, where the question is one of lot-to-lot consistency in performance, using nonphysiologic test conditions that match drug and dosage form properties with practical dissolution media and apparatus may be appropriate. However, where in vitro-in vivo correlations are desired, it is logical to consider and utilize knowledge of the in vivo condition. This publication critically reviews the literature that is relevant to oral human drug delivery. Physiologically relevant information must serve as a basis for the design of dissolution test methods and systems that are more representative of the human condition. As in vitro methods advance in their physiological relevance, better in vitro-in vivo correlations will be possible. This will, in turn, lead to in vitro systems that can be utilized to more effectively design dosage forms that have improved and more consistent oral bioperformance.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Mudie
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Amidon
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D001826:Body Fluids / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D004304:Dosage Forms; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D012995:Solubility
chemical_list: D004304:Dosage Forms
references.citation: Pharm Res. 1995 Mar;12(3):413-20
references.pmid: 7617530
references.citation: J Pharm Pharmacol. 2006 Aug;58(8):1079-89
references.pmid: 16872555
references.citation: Gut. 1986 Aug;27(8):886-92
references.pmid: 3732895
references.citation: Gut. 1988 Aug;29(8):1035-41
references.pmid: 3410329
references.citation: Dig Dis Sci. 1982 Nov;27(11):961-6
references.pmid: 7140493
references.citation: Eur J Pharm Biopharm. 2001 May;51(3):183-90
references.pmid: 11343881
references.citation: Am J Physiol. 1996 Jul;271(1 Pt 1):G172-83
references.pmid: 8760121
references.citation: Pharm Res. 1998 Feb;15(2):233-8
references.pmid: 9523309
references.citation: Gastroenterol Clin Biol. 1981 Apr;5(4):417-25
references.pmid: 7227749
references.citation: Gastroenterology. 1976 Feb;70(2):203-10
references.pmid: 2510
references.citation: Gastroenterology. 2010 Feb;138(2):469-77, 477.e1
references.pmid: 19909743
references.citation: Int J Pharm. 2005 Mar 23;292(1-2):17-28
references.pmid: 15725550
references.citation: Eur J Pharm Sci. 2005 Mar;24(4):297-303
references.pmid: 15734296
references.citation: Proc Biol Sci. 2004 Dec 22;271(1557):2587-94
references.pmid: 15615685
references.citation: J Lipid Res. 2008 Dec;49(12):2690-5
references.pmid: 18693215
references.citation: Pharm Res. 2009 Jun;26(6):1456-66
references.pmid: 19267186
references.citation: Pharm Res. 1986 Jun;3(3):123-31
references.pmid: 24271517
references.citation: Digestion. 1971;4(6):345-52
references.pmid: 5115090
references.citation: Eur J Drug Metab Pharmacokinet. 1998 Apr-Jun;23(2):97-102
references.pmid: 9725464
references.citation: Pharm Res. 1991 Mar;8(3):360-4
references.pmid: 2052525
references.citation: Dtsch Med Wochenschr. 1970 Oct 2;95(40):2011-6
references.pmid: 4919325
references.citation: J Biomech. 2007;40(6):1202-10
references.pmid: 16934271
references.citation: Am J Dig Dis. 1966 Jul;11(7):503-21
references.pmid: 5937767
references.citation: Aliment Pharmacol Ther. 2005 Nov 15;22(10):971-9
references.pmid: 16268972
references.citation: Eur J Pharm Sci. 2009 Jun 28;37(3-4):434-41
references.pmid: 19491035
references.citation: Food Chem Toxicol. 2001 Mar;39(3):209-28
references.pmid: 11278053
references.citation: Scand J Gastroenterol. 2006 Oct;41(10):1155-64
references.pmid: 16990200
references.citation: Eur J Pharm Biopharm. 2005 Aug;60(3):413-7
references.pmid: 15893920
references.citation: Gastroenterology. 1969 Apr;56(4):758-62
references.pmid: 5821083
references.citation: Clin Nutr. 2009 Dec;28(6):636-41
references.pmid: 19500889
references.citation: J Appl Physiol (1985). 1998 Nov;85(5):1941-8
references.pmid: 9804602
references.citation: J Pharm Sci. 1997 Mar;86(3):372-7
references.pmid: 9050808
references.citation: Gastroenterology. 1972 Apr;62(4):533-9
references.pmid: 5020865
references.citation: Gastroenterology. 1982 Apr;82(4):701-6
references.pmid: 7060888
references.citation: Pharm Res. 1998 Jan;15(1):11-22
references.pmid: 9487541
references.citation: Pharm Res. 2005 Aug;22(8):1215-26
references.pmid: 16078131
references.citation: Ann Acad Med Singap. 2008 Apr;37(4):347-53
references.pmid: 18461221
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Jun;280(6):G1227-33
references.pmid: 11352816
references.citation: Int J Pharm. 2000 Nov 4;208(1-2):61-70
references.pmid: 11064212
references.citation: Eur J Pharm Sci. 2010 Jan 31;39(1-3):15-22
references.pmid: 19837159
references.citation: Gut. 1971 Oct;12(10):863
references.pmid: 5123288
references.citation: Br Med J. 1972 Apr 8;2(5805):104-6
references.pmid: 5018285
references.citation: Gastroenterology. 1986 Apr;90(4):958-62
references.pmid: 3949122
references.citation: Mol Pharm. 2010 Oct 4;7(5):1527-32
references.pmid: 20726533
references.citation: Gut. 1984 May;25(5):491-9
references.pmid: 6714793
references.citation: Scand J Gastroenterol. 1971;6(4):313-7
references.pmid: 5561176
references.citation: Am J Physiol Gastrointest Liver Physiol. 2003 Nov;285(5):G1037-48
references.pmid: 12842820
references.citation: Pharm Res. 2008 Jul;25(7):1663-76
references.pmid: 18404251
references.citation: Eur J Pharm Biopharm. 2008 Sep;70(1):313-25
references.pmid: 18434110
references.citation: AAPS J. 2009 Jun;11(2):277-85
references.pmid: 19412669
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G159-63
references.pmid: 11408268
references.citation: Int J Pharm. 2008 Dec 8;364(2):213-26
references.pmid: 18602774
references.citation: Adv Drug Deliv Rev. 2005 Jun 15;57(8):1210-22
references.pmid: 15935870
references.citation: J Nutr. 2006 Apr;136(4):913-9
references.pmid: 16549450
references.citation: Gastroenterology. 1990 Nov;99(5):1275-82
references.pmid: 2210236
references.citation: J Am Acad Dermatol. 1985 Feb;12(2 Pt 1):308-12
references.pmid: 3838321
references.citation: Am J Physiol Gastrointest Liver Physiol. 2000 Apr;278(4):G604-16
references.pmid: 10762615
references.citation: Drug Dev Ind Pharm. 2003 Feb;29(2):231-9
references.pmid: 12648020
references.citation: Pharm Res. 2005 Apr;22(4):628-35
references.pmid: 15846471
references.citation: Scand J Gastroenterol. 1974;9(6):567-70
references.pmid: 4419676
references.citation: Aliment Pharmacol Ther. 2003 Nov 15;18(10):1039-48
references.pmid: 14616171
references.citation: Pharm Res. 1990 Jul;7(7):756-61
references.pmid: 2395805
references.citation: Pharm Res. 1996 Jan;13(1):163-7
references.pmid: 8668668
references.citation: Drug Dev Ind Pharm. 2007 Jun;33(6):595-605
references.pmid: 17613024
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 1):G553-8
references.pmid: 9277437
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8201-6
references.pmid: 20404209
references.citation: J Clin Gastroenterol. 2009 Jul;43(6):527-33
references.pmid: 19318982
references.citation: Clin Chim Acta. 1986 Sep 15;159(2):123-32
references.pmid: 3769204
references.citation: Pharm Res. 2005 Dec;22(12):2141-51
references.pmid: 16247711
references.citation: J Pharm Sci. 2006 Jan;95(1):116-25
references.pmid: 16315223
references.citation: J Nutr. 2000 Jan;130(1):122-7
references.pmid: 10613778
references.citation: J Pharm Sci. 2006 Feb;95(2):372-83
references.pmid: 16374852
references.citation: J Pharm Pharmacol. 2004 Apr;56(4):453-62
references.pmid: 15099440
references.citation: J Pharm Sci. 2009 Mar;98(3):1177-92
references.pmid: 18680176
references.citation: Int J Pharm. 2005 Feb 16;290(1-2):121-7
references.pmid: 15664137
references.citation: Pharm Res. 1997 Apr;14(4):497-502
references.pmid: 9144738
references.citation: Scand J Gastroenterol Suppl. 1975;32:11-144
references.pmid: 235788
references.citation: Crit Rev Food Sci Nutr. 2006;46(8):649-63
references.pmid: 17092830
references.citation: J Pharm Sci. 2008 Nov;97(11):4815-29
references.pmid: 18314890
references.citation: Pharm Res. 1998 May;15(5):698-705
references.pmid: 9619777
references.citation: AAPS J. 2006 Jan 03;7(4):E857-64
references.pmid: 16594638
references.citation: Gut. 1973 Jul;14(7):513-8
references.pmid: 4729918
references.citation: Int J Pharm. 2004 Jul 26;279(1-2):9-17
references.pmid: 15234789
references.citation: Digestion. 1968;1(2):65-77
references.pmid: 4877619
references.citation: Dig Dis Sci. 1987 May;32(5):472-80
references.pmid: 3646103
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Nov;297(5):G894-901
references.pmid: 19779010
references.citation: Eur J Pharm Sci. 2006 Nov;29(3-4):306-14
references.pmid: 16982177
references.citation: Gut. 1984 Apr;25(4):405-11
references.pmid: 6706220
references.citation: J Clin Invest. 1957 Oct;36(10):1521-36
references.pmid: 13475490
references.citation: Dig Liver Dis. 2004 Aug;36(8):505-12
references.pmid: 15334769
references.citation: J Clin Invest. 1971 Apr;50(4):890-900
references.pmid: 4926261
references.citation: Mol Pharm. 2009 Jan-Feb;6(1):29-39
references.pmid: 19183104
references.citation: Pharm Res. 2006 Jan;23(1):165-76
references.pmid: 16308672
references.citation: Pharm Res. 2000 Jul;17(7):891-4
references.pmid: 10990211
references.citation: J Pharm Pharmacol. 2007 Nov;59(11):1527-36
references.pmid: 17976264
references.citation: Gastroenterology. 1969 Sep;57(3):241-52
references.pmid: 5808483