Documentos de Académico
Documentos de Profesional
Documentos de Cultura
Stomach
pH = 1-3 (fasted)
pH = 4-7 (fed)
Duodenum
pH = 4-6
bile and pancreatic secretion
Jejunum
pH = 6-7, slightly lower in the fed state
Ileum
pH = 7-7.5
Colon
pH = 5-7
CLASS 1 CLASS 2
highly soluble poorly soluble
highly permeable highly permeable
CLASS 3 CLASS 4
highly soluble poorly soluble
poorly permeable poorly permeable
Guidance for Industry: Immediate release solid oral dosage forms, FDA, 1995
Class III:
Aciclovir: 1.3 mg/ml → D/S ca. 150 ml
neutral
ca. 20% bioavailability
Dr. Sandra Klein, 04/2008
Dissolution media for highly
soluble drugs (Class I and Class III)
• a simple medium is sufficient!
→ SGFsp pH 1.2
→ SIFsp pH 6.8
Specification
• > 85 % release within 30 min
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
Neutral substances
Danazol 0.5 µg/ml 200
Atovaquone 0.1 µg/ml (pKa 9) 1,785
Felodipine 1 µg/ml 10
Griseofulvin 15 µg/ml 16.6
Weak bases
Ketoconazole 4.7 µg/ml pKa 2.9; 6.5 44.4
Itraconazole < 0.001 µg/ml pKa 3.7 >> 100,000
Tamoxifen 3.3 µg/ml pKa 8.8 12
Sodium chloride 2g
Hydrochloric acid conc. 3g
Triton X 100 1g
Deionized water qs ad 1 liter
pH 1.8
Osmolality [mOsmol/kg] 120
Surface tension [mN/m] 31
Æ ENSURE PLUS®
Dr. Sandra Klein, 04/2008
In vitro simulation of the fasted SI
Fasted State Simulated Intestinal Fluid
FaSSIF
Sodium taurocholate 3 mM
Lecithin 0.75 mM
NaH2PO4 3.438 g
NaCl 6.186 g
NaOH qs ad pH 6.5
Deionized water qs ad 1 liter
pH 6.5
Osmolality [mOsmol/kg] ~ 270 *
Buffer capacity [mEq/pH/L] ~ 12
Surface tension [mN/m] 54
FeSSIF
Sodium taurocholate 15 mM
Lecithin 3 mM
Acetic acid 8.65 g
NaCl 11.874 g
NaOH pellets 4.04 g
Deionized water qs ad 1 liter
pH 5.0
Osmolality [mOsmol/kg] ~ 670*
Buffer capacity [mEq/pH/L] 72
Surface tension [mN/m] 48
SCoF pH 5.8
postprandial
preprandial
compendial
z preprandial
{ postprandial
Apparatus 2: 75 rpm
Time: 30 minutes
10
pH
Solubility [µg/ml]
1
1 2 3 4 5 6 7 8 9 10
0,1
0,01
0,001
0
10
20
30
40
50
60
W
at
SG er
Fs
p
U
SP
test media
28
SG
Fs
p
m
od
Ac .
et
at
e
bu
ffe
Bl r
an
k
Fa
SS
IF
Bl
an
k
Fe
SS
IF
Fa
Fe
SS
IF
Ac
et
at
e
Solubility of Phenytoin in different
bu
ffe
SI r
Fs
p
U
SP
2 8
Dissolution profiles of Phenytoin
in the fasted and the fed state
Phenytoin AWD 100 mg tablets
25 FeSSIF pH 5.0
20
% Release
FaSSIF pH 6.5
15
10
0
0 30 60 90 120 Blank FaSSIF pH 6.5
Time (min)
80
60
Release [%]
300 ml SGFsp
40 1000 ml FeSSIF
500 ml FaSSIF
900 ml SIFsp
20
0
0 20 40 60 80 100 120
Time [min]
z JB Dressman, GL Amidon, C Reppas, VP Shah. Dissolution testing as a prognostic tool for drug absorption:
immediate release dosage forms. Pharm. Res. 15: 11-22 (1998)
z E. Galia, J Horton, JB Dressman. Albendazole Generics – A comparative in vitro study. Pharm. Res.
16:1872-1876 (1999)
z R. Löbenberg, J Krämer, V Shah, GL Amidon, JB Dressman. Dissolution testing as a prognostic tool for drug
absorption: Dissolution behaviour of glibenclamide, a case II compound. Pharm. Res. 17: 439-444 (2000)
z JB Dressman, H Lennernäs. Oral Drug Absorption, Drugs and the pharmaceutical sciences Volume 106.
Marcel Dekker (www.dekker.com) ISBN 0-8247-0272-7. (2000)
z JB Dressman, J Butler, J Hempenstall, C Reppas. The BCS: Where do we go from here? Pharmacetutical
Technology 25: 68-76 (2001)
z S Klein. Biorelevant Dissolution Test Methods for Modified Release Dosage Forms. Doctoral Thesis. Institut
für Pharmazeutische Technologie. Frankfurt, Johann Wolfgang Goethe-Universität:
Shaker Verlag: ISBN 3-8322-4276-7 (2005).
z S Klein. J Butler, J Hempenstall, C Reppas, JB Dressman. Media to simulate the postprandial stomach I.
Matching the physicochemical characteristics of standard breakfasts. J Pharm Pharmacol 56(5): 605-10
(2004).
z S Klein, JB Dressman. Simplification of biorelevant media to prescreen solubility and dissolution performance
of poorly soluble drugs. Abstract, AAPS Annual meeting, Baltimore (2004)