Recent Advances in BCS and
Drug Product (BioPredictive)
Dissolution
Gordon L Amidon
College of Pharmacy
Charles Walgreen Jr. Professor of
Pharmacy
University of Michigan
Ann Arbor, MI 48109-1065
Moscow, Oct 28, 2013
Major Considerations in
Pharmaceutical Products
• Must Insure Labeling
• Must Insure Product Does What the Label
States
• Must Set Pharmaceutical Standards
– Insure Therapeutic Interchangeability
• World Market is Generic = Multi Source
Products
• Singular Fact: Patients Have (almost) No
Choice
Oral Drug Product Performance
Predicting Absorption(Fabs) vs. Systemic
Availability (Fsys)
Pharmaceutical Standards
• Identity
• Purity
– Safety and Efficacy
• Potency  Dose  Bioavailability
• BIOEQUIVALENCE!
Bioequivalence: Orange Book
Bioequivalent Drug Products. This term describes pharmaceutical equivalent or
alternative products that display comparable bioavailability when studied under similar
experimental conditions. Section 505 (j)(8)(B) of the Act describes one set of conditions
under which a test and reference listed drug5 shall be considered bioequivalent:
the rate and extent of absorption of the test drug do not show a significant difference
from the rate and extent of absorption of the reference drug when administered at the
same molar dose of the therapeutic ingredient under similar experimental conditions in
either a single dose or multiple doses; or
Bioavailability
(21 CFR 320)*
This term means the rate and extent
to which the active ingredient or
active moiety is absorbed from a
drug product and becomes available
at the site of action.
* Code of Federal Regulations (US Government)
Bioequivalence (BE): Today
Bioequivalence (BE) Paradigm
(Oral)
• Similar Plasma Levels  Similar Efficacy
• Similar In Vivo Dissolution  Similar
Plasma Levels
• Similar In Vitro Dissolution  Similar In
Vivo Dissolution
Bioavailability
(21 CFR 320)*
This term means the rate and extent
to which the active ingredient or
active moiety is absorbed from a
drug product and becomes available
at the site of action.
* Code of Federal Regulations (US Government)
General BE Confidence Interval
Test
Transport View of BE Science
BE connects the product in the
bottle with the claims on the label!
Label
“BE”
Product
BE: Transport (Absorptive) View
t
M (t )    P  C  dAdt
0 A
Transport Bioequivalence(BE)
If Two Drug Products, Same
Drug, present the drug to the
absorbing membrane the same
way, (C[x,y,z,t]), they will be
bioequivalent (BE)
Predicting Absorption
M (t ) 
tres

0
P

C

dAdt

A
Absorption Rate
dM / dt 
 P
m
 ( x, y, z )C m ( x, y, z )dA
A
• Same
Absorption Rate
• Same
metabolism rate
• Same Plasma
Levels
Oral BE and Dissolution
Amidon et al., Clinical pharmacology and Therapeutics, 90, 467 (2011)
The Case for ‘Dissolution’
Bioperformance Dissolution
• Phase III Clinically
tested Product
• In Vivo Dissolution
of Phase III Product
= Bioperformance
Dissolution
• In Vitro
Dissolution?
Amidon, KS, et al. Clin. Pharmac. Therap., 90, 467, 2011
August 2000 FDA Guidance
G.L. Amidon et. al., Pharmaceutical Research, 12,
413 (1995).
Biopharmaceutical Classification
High
Permeability
Low Solubility
Class 1
Class 2
High Solubility
High Permeability
(Rapid
Dissolution)
Low Solubility
High Permeability
Low
Permeability
High Solubility
Class 3
Class 4
High Solubility
Low Permeability
Low Solubility
Low Permeability
Amidon et al., Pharm Res 12: 413-420, 1995
BCS: Definitions
• High Permeability Fraction Absorbed>90% (85%)
– Permeability is Surrogate (Human/Animal/Caco2)
• High Solubility->Highest Dose Soluble 250 ml
– pH 1-7.5 (6.8), pKa
High Permeability Drug:
Fabs>90%
Fabs
High Solubility Drug
FDA Glass of Water= 8 oz.
(240 ml)
• Vs = Volume of Solution
<250 ml,
• pH=1-7.5 (6.8)
• Highest Dose Strength
• Do=Dose/250/C s <1
BCS of Worlds Drugs
Drug database of oral immediate-release (IR) drugs
on 200 top-selling US, GB, ES, JP, and KR drug
products
• US: 113 oral IR drugs (56.5%)
• GB: 102 oral drugs (51.0%)
• ES: 106 oral drugs (53.0%)
• JP: 113 oral drugs (56.5%)
• KR: 87 oral drugs (43.5%)
• Based on 200 top-selling drug products in 5 countries, and WHO Essential
drugs (EML), drug databases of Combined List (346 drugs), Western List
(147 drugs), Eastern List (163 drugs) was made and analyzed on molecular
properties and BCS classification.
Comparison of the percentage of oral IR drugs of permeability class on the
Combined, Western, Eastern, US, GB, ES, JP, KR, and WHO lists
0
Combined
Western
Eastern
US
GB
ES
JP (150mL)
JP (250mL)
KR (240mL)
KR (250mL)
WHO
Combined
Western
Eastern
US
GB
ES
JP (150mL)
JP (250mL)
KR (240mL)
KR (250mL)
WHO
Combined
Western
Eastern
US
GB
ES
JP (150mL)
JP (250mL)
KR (240mL)
KR (250mL)
WHO
Percentage of oral IR drugs
Comparison of the percentage of oral IR drugs of solubility class in the
Combined, Western, Eastern, US, GB, ES, JP, KR, and WHO lists
60
50
40
30
20
10
High-solubility
Low -solubility
Unavailable
BCS Worlds Drugs
Bioperformance Dissolution
(Definition)
• An in vitro dissolution methodology that is
predictive of in vivo dissolution
• This methodology is not a QC methodology
• It is not a regulatory methodology
• It IS a drug product development
methodology
Bioperformance Dissolution Sub-Classification
Proposal
BCS
Class
I
Drug Solubility
pH 1.2
Drug Solubility
pH 6.8
Drug
Permeability
High
High
High
Preferred Procedure
>85% Dissolution in 15 min; 30 min, f2., pH =
6.8.
15 min at pH=1.2, then 85% Dissolution in 30
min., pH = 6.8; F2>50; 5 points minimum; not
more than one point > 85%.
II-A
Low
High
High
II-B
High
Low
High
>85% Dissolution in 15 min., pH = 1.2.
II-C
Low
Low
High
15 min at pH=1.2; then 85% Dissolution in 30
min., pH = 6.8 plus surfactant*; F2>50; 5 points
minimum, not more than one point > 85%.
III
High
High
Low
>85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8.
IV-A
Low
High
Low
15 min. at pH = 1.2; then 85% Dissolution in 30
min., pH = 6.8,; F2>50; 5 points minimum.; not
more than one point > 85%.
IV-B
High
Low
Low
>85% Dissolution in 15 min., pH = 1.2.
IV-C
Low
Low
Low
15 min at pH=1.2; then 85% Dissolution in 30
min., pH = 6.8 plus surfactant*; F2>50; 5 points
minimum, not more than one point > 85%.
Bioperformance Dissolution: One
Consideration
•
•
•
•
•
GI Physiology
pH
Buffer
Transit
Fasted/Fed
Human In Vivo Buffer: Bicarbonate
Human GI Bicarbonate
Pharmaceutical
buffers
10mM
Stomach
4-21mM,
Average= 15mM
30mM
pH 1.2, 0.1N HCl
1. USP
2. FaSSIF
3. Others
70mM
J.G. Hardman, et al., eds., Goodman and Gilman’s The pharmacological basis for therapeutics, 10th ed., Chapter 39, p1038.
N.W. Tietz, et al., eds., Clinical guide to laboratory tests., 3rd ed., p 84.
W. G. Karr, et al., Intubation Studies Of The Human Small Intestine. Iv. Chemical Characteristics Of The Intestinal Contents In
The Fasting State And As Influenced By The Administration Of Acids, Of Alkalies And Of Water. J Clin Invest 14: 893-900
(1935).
A Pharmaceutical Product with CO2
2012 Sales
16
14
12
10
8
6
4
2
0
Coke Cola
Pfizer
CO2 in the Environment
Pharmaceutical Buffers
• United State Pharmacopeias (USP) buffer
– 50 mM pH 6.8 phosphate buffer

Fasted State Simulated Small Intestinal Fluids (FaSSIF1)






Other buffers covering pH 1.2-7.5




1:
29 mM NaH2PO4
q.s. to pH 6.5 with NaOH
3 mM Na taurocholate
0.75 mM lecithin
106 mM NaCl
Simulated gastric fluids (SGF): pH 1.2 HCl
FeSSIF (Fed State Simulated Small Intestine fluids) pH 5.0 acetate buffer
pH 7.5 phosphate buffer
Buffer choice of analytical chemists with addition of SLS, Tween, and CTAB.
Vertzoni M. et al., Dissolution media simulating the intralumenal composition of the small intestine:
physiological issues and practical aspects. J. Pharmacy & Pharmacology, 2004, 56:453-462.
Equilibrium (?) In the Intestine
CO2 (g)
•
Bicarbonate Equilibrium
•
•
•
H2CO3 HCO3− + H+
Ka1 = 2.5×10−4 ; pKa1 = 3.60 at 25 °C.
HCO3− CO32− + H+
Ka2 = 5.61×10−11 ; pKa2 = 10.33 at 25 °C
•
•
Gas Phase Equilibrium
•
–
•
•
•
•
•
•
•
CO2(gas) = CO2(dissolved)
where kH=29.76 atm/(mol/L) at 25°C (Henry constant)
CO2(aq) + H2O = H2CO3 (aq)
Then of course we have CO2 transport in the Intestine
Transporters, Exchangers, intracellular equilibrium
PCO2 (Intestine)~200 mmHg
CO2 (aq) + H2O =
H2CO3
Bicarbonate Buffer Physiological
Relevance
• Bicarbonate is secreted
by the cells throughout
the GI tract.
• Bicarbonate in the
lumen of the GI tract
modulates luminal pH.
GI Lumen
𝑪𝑶𝟐 + 𝑯𝟐 𝑶 ⇌ 𝑯+ + 𝑯𝑪𝑶𝟑−
𝑪𝑶𝟐 + 𝑯𝟐 𝑶 ⇌ 𝑯+ + 𝑯𝑪𝑶𝟑−
GI Epithelial Cell
Blood
Bicarbonate Buffer: Reactions and Rates
𝑲𝟎
𝑲𝟏
CO2 𝒂𝒒 + 𝑯𝟐 𝑶 ⇌ 𝑯𝟐 𝑪𝑶𝟑 ⇌ 𝑯+ + 𝑯𝑪𝑶𝟑−
𝑯𝟐 𝑪𝑶𝟑
𝑲𝟎 =
𝑪𝑶𝟐 𝒂𝒒
𝑯 + 𝑯𝑪𝑶−
𝟑
𝑲𝟏 =
𝑯𝟐 𝑪𝑶𝟑
𝑲𝒉
𝑲𝟎 =
𝑲𝒅
𝑲𝒇
𝑲𝟏 =
𝑲𝒓
𝑲𝒉 = ~𝟎. 𝟏 𝒔−𝟏
𝑲𝒇 = 𝟖 × 𝟏𝟎𝟔 𝒔−𝟏
Th=1/.1=10 ses
𝑲𝒅 = ~𝟓𝟎 𝒔
−𝟏
Td=1/50=0.02 sec
𝑲𝒂 = 𝑲𝟎 ∙ 𝑲𝟏 = 𝟏𝟎−𝟐.𝟔 ∙
𝑲𝒓 = 𝟒. 𝟕 × 𝟏𝟎𝟏𝟎 𝒔−𝟏
+ 𝑯𝑪𝑶−
𝑯
𝟑
𝟏𝟎−𝟑.𝟕
𝑪𝑶𝟐 𝒂𝒒
= 10-6.3
Film Model Flux and Flux using
Cussler’s Reaction Enhancement Factor
Flux with Reaction
Enhancement Factor
Film Model Flux
𝑘 0 𝐻2 𝐶𝑂3
0
− 𝐻2 𝐶𝑂3
𝑘 𝐻2 𝐶𝑂3
ℎ
𝐷𝐻2 𝐶𝑂3
𝑘 =
ℎ
𝑘=
0
𝐷𝐻2 𝐶𝑂3
𝐻2 𝐶𝑂3
0
− 𝐻2 𝐶𝑂3
ℎ
𝑘0
50
100
250
500
10,000
2.384 x 10−3
3.372 x 10−3
5.331 x 10−3
7.54 x 10−3
3.38 x 10−2
− 𝐻2 𝐶𝑂3
ℎ
𝐷𝐻2 𝐶𝑂3 𝑘𝑑
𝐷𝐻2 𝐶𝑂3 𝑘𝑑 𝐻2 𝐶𝑂3 0 − 𝐻2 𝐶𝑂3
ℎ
RPM
0
𝑘
3.42
3.42
3.42
3.42
3.42
x
x
x
x
x
10−2
10−2
10−2
10−2
10−2
EL Cussler, “Diffusion and Mass Transport”, 2009, Wiley
𝑘
𝑘0
14.344
10.143
6.415
4.536
1.013
ℎ
Ф
(Best Fit)
17
14
5.6
2.8
nd
Predicted and Experimental Flux in Bicarbonate
Buffer at pH 6.5: Ibuprofen
Solubility=3.3x10-4 M, pKa=4.43, Diffusion Coefficient =7.93x10-6 cm2/s
0.4
Experimental in Bicarbonate Buffer
0.35
Predicted in Bicarbonate Buffer
(pKa = 6.3)
Flux (mg/cm^2/min)
0.3
Predicted in Bicarbonate (Based on
Reaction Enhancement Factor phi)
0.25
Predicted in Bicarbonate Buffer
(pKa = 3.7)
0.2
0.15
0.1
0.05
0
0
5
10
15
Bicarbonate Buffer Concentration (mM)
20
25
BABE 1960-Present
• Mainly Empirical: Cmax and AUC
– Regulatory Dominated
• Little Biopharmaceutical Mechanism
– ADME very complex-> Empirical
• Pharmacokinetics Dominated the Science
– Analytical and Computational Technology
• Regulatory Standards from the ~1970’s
– BA & BE
Bioequivalence (BE) Today: Oral
• Historically a Relative Bioavailability (BA)
Based View
– Misses the underlying scientific issues
• IN Vivo Dissolution
• BE Testing is Same Drug
– Once Absorbed PK is the Same
• The Science of BE is at the Absorption Site
– For Oral Dosage Form in the GI Tract
• The Question is: What is the Best BE Test
BioPredictive Dissolution (BPD)
• BCS Class I, IIa, III
– Rapid Dissolution
• BCS Class IIb,c
– More Complex
• Modified Release
– -Move Complex
天獄
地獄の辺土(天国と地獄の間)
煉獄(苦行)
地獄
Predicting Absorption
M (t ) 
tres

0
P

C

dAdt

A
Time Dependent Absorption
M (t ) 
tres
  P  C  dAdt
0
A
dC / dt  k a  C
( dM / dt )1 / V 
dC / dt  ka  C
(dM / dt )1/ V 
 ka  C  ka  C
ka (t )  1/ sec
 k a  C  k a  C
k a ( t )  1 / sec
Diffusion vs. Pharmacokinetic Views of
Absorption: A Simpler Well Mixed View
Diffusion
J  (dM / dt )1/ A
 P  C  P  C
Pharmacokinetic
dC / dt  (dM / dt )1/ V
 ka  C  ka  C
ka  1/ sec
P  cm / sec.
ka  ( S / V )  Peff
Software e.g. GastroPlus®
Predicting Absorption(Fabs) vs. Systemic
Availability (Fsys)
Predicting Absorption
M (t ) 
tres

0
P

C

dAdt

A
Transport View Of Oral
Absorption