Impact of Buffer on Dissolution:
In vivo Relevance
Gregory E. Amidon
Brian J. Krieg
Gordon L. Amidon
University of Michigan
College of Pharmacy
NIPTE: A Decade of Scientific Excellence
April 30-May 1, 2015
Rockville, MD
1
Bicarbonate as a physiological buffer?
•
•
•
•
It is physiologic
It is the major (perhaps not the only) buffer in the GI
It is not well characterized or understood (at least in the
pharma world)
It is challenging to work with
All the ingredients
(CO2 and
H2O) are
readily
available to
all biological
systems
free of
charge.
What can we do about it?
•
•
•
2
We can understand it better
What would an equivalent buffer be?
• Phosphate?
•
•
Concentration?
pH?
Can we benefit by identifying or using an “equivalent buffer”?
Factors Affecting “In Vivo” Dissolution to
be discussed today are:
•
•
3
GI Environmental / Physiological Factors
•
•
•
•
•
•
pH
Buffer species and concentration
GI fluid hydrodynamics
Intestinal motility
Bile salts
Volume, temperature, and viscosity, etc.
Drug Properties:
•
•
•
Solubility
pKa (acids and bases)
Particle size
Dissolution Testing: The Future
•
Need to transition to multiple dissolution methodologies for
different purposes (eg: fit for purpose dissolution methodologies)
• Quality control (eg: Good, Fast, and Cheap; appropriate for material and
process control)
•
In Vivo Predictive (eg: QbD purposes: assess CMA, CPP, CQA; not
necessarily Fast or Cheap)
Need to “take into account” buffer, buffer capacity, drug pKa, drug solubility, pH,
pH changes, hydrodynamics, absorption, etc
•
Need to consider BCS Class in selecting appropriate dissolution
methodologies from several options
• Current compendial methods (eg: Apparatus I, II, IV)
• Multicompartment systems: Gastrointestinal Simulators (eg: GIS, ASD)
• Multiphase systems: (eg: Biphasic)
Need to “take into account” drug pKa (acid(a), base (b), neutral (c)), solubility,
buffer, buffer capacity, pH, pH changes, absorption, etc.
4
Bicarbonate Buffer is One Important Component in
Developing an In Vivo Predictive Dissolution Method
•
•
•
•
5
CO2(aq) reacts with water
_ to
form bicarbonate (HCO3 )
and (H+) .
Bicarbonate is secreted by
the epithelial cells
throughout the GI tract to
modulate luminal pH.
Bicarbonate reacts with H+ in
the lumen to form CO2 and
H2O
Carbonic Anhydrase (CA)
catalyzes the relatively slow
_
conversion of CO2 to HCO3
GI Lumen
𝑪𝑶𝟐 + 𝑯𝟐 𝑶 ⇌ 𝑯+ + 𝑯𝑪𝑶𝟑−
CA XIV
𝑪𝑶𝟐 + 𝑯𝟐 𝑶
𝑪𝑨 𝑰𝑰
𝑯+ + 𝑯𝑪𝑶−
𝟑
GI Epithelial Cell
Blood
Carbon Dioxide in the GI Tract
•
•
The CO2 concentration is between 4-10 % in
the stomach of healthy humans (%v/v at 1 atm).
In the duodenum, these values are typically
significantly higher and can be as high as 66%
CO2(g).
𝑪𝑶𝟐 (𝒈) ⇌ 𝑪𝑶𝟐 (𝒍) + 𝑯𝟐 𝑶 ⇌ 𝑯+ + 𝑯𝑪𝑶−
𝟑
•
6
•
•
•
•
In the jejunum, the average %CO2 is ~13% at
pH ~ 6.5.
Sjoblom M 2011. Acta Physiologica 201:85-95.
Brinkman A, et.al. 2001. Am J Respir Crit Care Med 163:1150-1152.
McGee LC, Hastings AB 1942. J Biol Chem 142:893-904.
Rune S 1972. Gastroenterology 62:533-539
Bulk Bicarbonate Buffer Considerations
•
•
At physiological pH(~ 6.5) and % CO2 (~13-15%)
•
CO2/Bicarbonate Buffer concentration ([CO2]+[HCO3-]) is about 14 mM with a buffer
capacity of  ~6 mmol H+ /L/pH
USP buffer:
•
50 mM phosphate at pH 6.5 buffer capacity  ~25 mmol H+ /L/pH
Total Buffer Concentration, [CO2] + [HCO3-] (mM),
Buffer Capacity,  , in parentheses (mmol H+ /L/pH)
% CO2
pH
5%
7
5.5
6
6.5
7
7.5
4.7
12.2 (2.49)
35.0 (2.67)
10%
15%
4.6
9.3 (4.10)
6.9
14.0 (6.16)
24.3
36.5
71.7
20%
9.2
18.7
40%
12.4
18.4
60%
18.6 (7.42)
27.6
Bicarbonate Buffer System:
Reactions and Kinetics
CO2 𝒂𝒒 + 𝑯𝟐 𝑶 ⇌ 𝑯𝟐 𝑪𝑶𝟑 ⇌ 𝑯+ + 𝑯𝑪𝑶−
𝟑
8
Bicarbonate Buffer: Reactions and Rates
𝑲𝒉
CO2 𝒂𝒒 + 𝑯𝟐 𝑶 ⇌ 𝑯𝟐 𝑪𝑶𝟑
𝑲𝒅
𝑲𝟎 =
−
+
𝑯𝟐 𝑪𝑶𝟑 ⇌
𝑯
+
𝑯𝑪𝑶
𝟑
𝑲
𝒓
𝑯 + 𝑯𝑪𝑶𝟑−
𝑲𝟏 =
𝑯𝟐 𝑪𝑶𝟑
𝑯𝟐 𝑪𝑶𝟑
𝑲𝟎 =
𝑪𝑶𝟐 𝒂𝒒
𝑲𝒉
𝑲𝒅
𝑲𝒇
~ 10-2.6
𝑲𝟏 =
𝑲𝒇
𝑲𝒓
~ 10-3.5
𝑲𝒉 ~ 𝟎. 𝟏 𝒔−𝟏
𝑲𝒇 ~ 𝟖 × 𝟏𝟎𝟔 𝒔−𝟏
𝑲𝒅 ~ 𝟓𝟎 𝒔−𝟏
𝑲𝒓 ~ 𝟓 × 𝟏𝟎𝟏𝟎 𝒔−𝟏
𝑲𝒂 = 𝑲𝟎 𝑲𝟏 ~ 10-6.04
Carbonic anhydrase (CA) catalyzes both the hydration and
dehydration of carbon dioxide.
9
Simultaneous Diffusion and
Chemical Reaction Model
10
Applying the Film Model to Rotating Disk
Dissolution (eg: weak acid drug)
HCO3
CO2
HCO3
CO2
pH=6.5
𝑫𝒊𝒇𝒇𝒖𝒔𝒊𝒐𝒏 𝑳𝒂𝒚𝒆𝒓 𝒕𝒉𝒊𝒄𝒌𝒏𝒆𝒔𝒔 = 𝒉
= 𝟏. 𝟔𝟏𝑫𝟏/𝟑 𝝎−𝟏/𝟐 𝒗𝟏/𝟔
11
Mooney K, et al. V 1981. J Pharm Sci 70(1):22-32.
Levich VG. 1962. Physicochemical Hydrodynamics. ed., New jersey: Prentice Hall.
Film Model: Bicarbonate Buffer
𝐻 + + 𝑂𝐻 − ⇌ 𝐻2 𝑂
Boundary Conditions at X = h:
𝐻𝐴 ⇌ 𝐻 + + 𝐴−
𝐻𝐴 = 𝐻𝐴
𝐻𝐴 + 𝑂𝐻− ⇌ 𝐻2 𝑂 + 𝐴−
𝐴− = 𝐴−
𝐻𝐴 + 𝐻𝐶𝑂3− ⇌ 𝐶𝑂2 + 𝐻2 𝑂 + 𝐴−
𝐻+ = 𝐻+
𝐶𝑂2 + 𝐻2 𝑂 ⇌ 𝐻𝐶𝑂3− + 𝐻 +
𝑂𝐻− = 𝑂𝐻−
𝛿 [𝐻𝐴]
= 𝐷𝐻𝐴
𝛿𝑡
𝛿 𝐴−
𝛿𝑡
= 𝐷𝐴
𝛿 𝐻+
𝛿𝑡
= 𝐷𝐻
𝛿 𝑂𝐻 −
𝛿 𝐻𝐶𝑂3−
𝛿 𝐶𝑂2
𝛿𝑡
𝛿𝑋2
𝛿 2 𝐴−
𝛿 2 𝐻+
𝛿𝑋2
= 𝐷𝐶𝑂2
+ ∅1 = 0
+ ∅3 = 0
𝛿 2 𝑂𝐻 −
𝛿𝑋2
= 𝐷𝐻𝐶𝑂3
𝛿2
+ ∅4 = 0
𝛿 2 𝐻𝐶𝑂3−
𝛿𝑋2
𝐶𝑂2
𝛿𝑋2
ℎ
ℎ
≅0
(𝑘𝑛𝑜𝑤𝑛)
𝐻𝐶𝑂3− = 𝐻𝐶𝑂3−
+ ∅2 = 0
𝛿𝑋2
= 𝐷𝑂𝐻
𝛿𝑡
𝛿𝑡
𝛿 2 [𝐻𝐴]
≅0
ℎ
+ ∅5 = 0
+ +∅6 = 0
𝐶𝑂2 = 𝐶𝑂2
ℎ
(𝑘𝑛𝑜𝑤𝑛)
ℎ
ℎ
(𝑘𝑛𝑜𝑤𝑛)
(𝑘𝑛𝑜𝑤𝑛)
Boundary Conditions at X = 0:
𝐻𝐴 = 𝐻𝐴
𝐴− = 𝐴−
𝐻+ = 𝐻+
(𝑊𝑒𝑎𝑘 𝑎𝑐𝑖𝑑 𝑖𝑛𝑡𝑟𝑖𝑛𝑠𝑖𝑐 𝑆𝑜𝑙𝑢𝑏𝑖𝑙𝑖𝑡𝑦)
0
0
0
(𝑈𝑛𝑘𝑛𝑜𝑤𝑛)
(𝑈𝑛𝑘𝑛𝑜𝑤𝑛)
𝑂𝐻− = 𝑂𝐻−
0
𝐻𝐶𝑂3− = 𝐻𝐶𝑂3−
𝐶𝑂2 = 𝐶𝑂2
0
(𝑈𝑛𝑘𝑛𝑜𝑤𝑛)
0
(𝑈𝑛𝑘𝑛𝑜𝑤𝑛)
(𝑈𝑛𝑘𝑛𝑜𝑤𝑛)
∆ 𝑭𝒍𝒖𝒙 𝑶𝑯− 𝒊𝒏 + ∆ 𝑭𝒍𝒖𝒙 𝑯𝑪𝑶𝟑− 𝒊𝒏 = ∆ 𝑭𝒍𝒖𝒙 𝑯𝑨 𝒐𝒖𝒕 + ∆ 𝑭𝒍𝒖𝒙 𝑯+ 𝒐𝒖𝒕
𝑱𝒕𝒐𝒕𝒂𝒍 = 𝑱𝑯𝑨 + 𝑱𝑯 + 𝑱𝑶𝑯 + 𝑱𝑯𝑪𝑶 𝟑
12
Ref: Mooney K, et al. V 1981. J Pharm Sci 70(1):22-32.
Is the slow hydration (and dehydration) reaction a problem?
Average lifetime of a molecule in the DL is ~ 0.4 sec at 100 rpm (DL~40 )
𝒕𝑫𝒊𝒇𝒇𝒖𝒔𝒊𝒐𝒏
𝒉𝟐
=
𝟐𝑫
The time it takes for the reaction to occur in the DL (63% complete)
𝟏
𝒕𝒓𝒆𝒂𝒄𝒕𝒊𝒐𝒏 =
𝒌
~ 5-10 sec for the hydration reaction: 𝑪𝑶𝟐 𝒂𝒒 + 𝑯𝟐 𝑶 → 𝑯𝟐 𝑪𝑶𝟑
~ 0.01 - 0.02 sec for the dehydration reaction: 𝑪𝑶𝟐 𝒂𝒒 + 𝑯𝟐 𝑶 ← 𝑯𝟐 𝑪𝑶𝟑
In the diffusion layer:
• Hydration reaction is too slow to be important
• Dehydration reaction is fast enough to occur
13
Mooney KG et al. 1981. JPharmSci 70(12):1358-1365. Higuchi, etal, 1917 Farm. Aikak 80, 55.
Brian and the Three Models
Includes Both hydration and
dehydration
Includes Neither
hydration or dehydration
Includes Only dehydration
Bulk Chemical Equilibrium
(BCE)
Carbonic Acid Ionization
(CAI)
Irreversible Dehydration Reaction
(IRR)
𝐾0
𝐾1
+
𝐶𝑂2 𝑎𝑞 + 𝐻2 𝑂 𝐻2 𝐶𝑂3 𝐻 +
pKa1 = K0*K1= 6.04
𝐻𝐶𝑂3−
𝐾1
𝐻2 𝐶𝑂3 𝐻
+
+ 𝐻𝐶𝑂3−
pK1 = 3.55
𝑘𝑑
𝐾1
𝐶𝑂2 𝑎𝑞 + 𝐻2 𝑂 𝐻2 𝐶𝑂3 𝐻 + + 𝐻𝐶𝑂3−
Kd = 50 sec-1
pK1 = 3.55
Kh = 0 sec-1
eg: Mooney, Stella, etal
eg: Mooney, Stella, etal
eg: Krieg, etal
For each of these three models, we can solve for pH at the
dissolving surface and the resulting dissolution rate.
Ref: 1. Mooney, K., Mintun, M., Himmelstein, K., and Stella, V. (1981) J. Pharm. Sci. 70, 22-32
2. Krieg, B. J., Taghavi, S. M., Amidon, G. L., and Amidon, G. E. (accepted for publication July 2014) J Pharm Sci
14
Experimental Setup: CO2-bicarbonate buffer
Rotating Disk
Air & CO2 flow rates adjusted
to obtain 5-20% CO2
Dissolved
CO2 Monitor
Air CO2
pH
Drug
5-20% CO2
15
Predicted and Experimental Flux: Ibuprofen (Weak acid)
Solubility=3.3x10-4 M, pKa=4.43, Diffusion Coefficient =7.9x10-6 cm2/s
Buffer Conc.
0.1
BCE
0.35
0.6
BCE
0.25
Flu x (mg /cm^2/min )
0.06
0.04
0.5
0.02
0.25
0
0
0.4
0.2
Flux (mg/cm^2/min)
Flux (mg/cm^2/min)
0.3
Phosphate Buffer
(BCE model)
0.15
IRR
0.1
0.05
CAI
0
-10
10
30
Buffer Concentration (mM)
50
pH
BCE
0.08
0.3
16
(Rotation Speed)1/2
Flux (mg/cm^2/min)
0.4
1
2
3
4
5
6
7
8
Rad/S ^1/2
0.3
0.2
0.2
0.15
0.1
IRR
IRR
0.05
CAI
0
0.1
0
0
1
2
3
100RPM
4
Rad/S ^1/2
5
6
7
500RPM
8
CAI
5.2
5.4
5.6
5.8
6
pH
6.2
6.4
6.6
6.8
The experimental and predicted flux of ibuprofen in bicarbonate buffer at multiple concentrations (at pH 6.5 and 37 oC),
at different rotating disk speeds, and as different pH. Key: () Experimental Bicarbonate buffer. () BCE=Bulk Chemical
Equilibrium model, CAI = Carbonic Acid Ionization model, IRR=Irreversible Reaction model.
7
Predicted and Experimental Flux at pH 6.5: Ketoprofen & Indomethacin
0.9
0.04
Flux (mg/cm^2/min)
Flux (mg /cm^2/min)
BCE
0.8
0.7
0.6
0.5
0.4
0.3
IRR
0.2
CAI
0.1
BCE
0.03
0.025
0.02
IRR
0.015
0.01
0.005
CAI
0
0
0
50
Buffer Concentration (mM)
Ketoprofen (Weak acid)
x10-4
Solubility=5.3
M, pKa=4.02,
Diffusion Coefficient =9.3x10-6 cm2/s
17
0.035
100
0
5
10
15
20
25
Bicarbonate Buffer Concentration (mM)
Indomethacin
30
35
40
(Weak acid)
Solubility=5.96x10-6 M, pKa=4.27, Diffusion
Coefficient =6.8x10-6 cm2/s
The experimental and predicted flux of Ketoprofen in bicarbonate buffer at multiple concentrations (at pH 6.5 and 37 oC).
Key: ( • ) Experimental
Predicted and Experimental Flux at pH 6.5: Haloperidol (Weak base)
Solubility=8.5x10-6 M, pKa=8.0, Diffusion Coefficient =6.6x10-6 cm2/s
0.035
Flux (mg /cm^2/min)
0.03
Flux (mg/cm^2/min)
0.025
BCE
0.02
0.015
IRR
0.01
CAI
0.005
Buffer Conc.
0.012
pH
BCE
0.01
50 mM phosphate buffer
(BCE model)
0.008
IRR
0.006
0.004
CAI
0.002
0
0
0
6
6.5
7
pH
7.5
10
20
30
40
Buffer Concentration (mM)
The experimental and predicted flux of haloperidol in bicarbonate as a function of pH and buffere concentration at
37oC. Key ( ) Experimental Flux in Bicarbonate Buffer and () phosphate buffer.
18
50
A Phosphate Buffer to Equivalent 15% CO2
(10.4 mM HCO3- ) is Possible!
Weak Acids
19
@
pH=6.5
Weak Bases
Is an “equivalent phosphate buffer” actually equivalent
to physiologically relevant bicarbonate buffer in USP 2?
120
• Drug = 200 mg of 235 um
diameter ibuprofen particles
(suspension)
• 11 mM bicarbonate buffer
• pH = 6.5 for ibuprofen
% Dissolved
• 3.5 mM phosphate buffer
Bicarbonate buffer
100
80
Phosphate buffer
60
40
• USP Apparatus 2, 50 rpm, 900 mL
20
0
0
20
40
Time (Minutes)
20
60
Is an “equivalent phosphate buffer” actually equivalent
to physiologically relevant bicarbonate buffer in USP 2?
• Tablet is pre-disintegrated in 0.01
N HCl before adding to dissolution
vessel
• 3.5 mM phosphate buffer
• 11 mM bicarbonate buffer
• pH = 6.5 for ibuprofen
• USP Apparatus 2, 50 rpm, 900 mL
120
Phosphate buffer
100
% Dissolved
• Drug Product = 200 mg
commercially available, film-coated
ibuprofen tablet (Motrin IB)
80
Bicarbonate buffer
60
40
20
0
0
10
20
30
Time (Minutes)
21
40
50
Is an “equivalent phosphate buffer” actually equivalent
to physiologically relevant bicarbonate buffer in USP 2?
• Drug Product = 200 mg
commercially available, film-coated
ibuprofen tablet (Motrin IB)
120
Bicarbonate buffer
• Tablet is introduced intact into
dissolution vessel
• 3.5 mM phosphate buffer
• 11 mM bicarbonate buffer
• pH = 6.5 for ibuprofen
% Dissolved
100
80
Phosphate buffer
60
40
20
• USP Apparatus 2, 50 rpm, 900 mL
0
0
20
40
Time (Minutes)
22
60
Predicted Dissolution rate per cm2 (Flux, Rotating Disk Method) in
Physiologically Relevant Bicarbonate Buffer, USP Dissolution Media,
USP Simulated Intestinal Fluid, and FaSSIF
Buffer Conc.
Buffer
Species
pH
Ibuprofen Flux
mg/cm2/min
Physiologically
Relevant
Bicarbonate
Physiologically
Relevant
Phosphate
11 mM
USP
USP
monograph
test
3.5 mM
50 mM
10 mM
50 mM
28.7 mM
Bicarbonate
Phosphate
Phosphate
Phosphate
Phosphate
Phosphate
6.5
6.5
7.2
7.2
6.8
6.5
0.06
0.06
0.71
0.48
0.22
1
11.9 x
8.0 x
3.7 x
0.092
0.066
0.033
7 x
5 x
2.5 x
Ratio
Ratio
(bicarb/phosphate)
1Galia,
FaSSIF1
w/o
surfactants
monograph
test
(bicarb/phosphate)
Indomethacin
Flux mg/cm2/min
USP
Simulated
Intestinal
Fluid
0.013
E.; Nicolaides, E.; Horter, D.; Lobenberg, R.; Dressman, J. B. Evaluation of various dissolution media for predicting
in vivo performance of class I and II drugs. Pharmaceutical research 1998, 15, (May), 698.
23
Conclusions
24
•
Buffers that undergo instantaneous reversible chemical reactions (eg:
phosphate buffer) are predicted accurately by a simultaneous diffusion and
chemical reaction model (eg: Mooney, etal (1981)).
•
The Irreversible Reaction Rate (IRR) accounting for the slow reaction rate
between CO2 and H2O accurately predicts dissolution of weak acids and weak
bases for bicarbonate buffer.
•
Matching the dissolution rate of drugs in phosphate and bicarbonate buffer
systems is possible.
•
In general, the buffer capacity of 50 mM phosphate (pH=6.5-6.8) is substantially
greater than physiologically relevant bicarbonate buffer.
•
Low phosphate buffer concentrations (~5-30 mM) are expected to better
simulate physiologically relevant bicarbonate buffer concentrations (based on
rotating disk method).
•
An equivalent phosphate buffer varies depending on drug properties
(acid, base, pKa, solubility)
Future Work:
•
Test and demonstrate relevance of buffer type and
capacity using
•
In vivo predictive dissolution methodology(ies)
•
In vivo “data”
•
Address some of the technical challenges in using
bicarbonate buffer
•
Address some of the technical challenges in using an
equivalent (eg: phosphate) buffer
•
25
Low buffer capacity buffer matches surface pH conditions but not
“bulk” buffer conditions.
Dissolution Testing: The Future
•
Need to transition to multiple dissolution methodologies for
different purposes (eg: fit for purpose dissolution methodologies)
• Quality control (eg: Good, Fast, and Cheap; appropriate for material and
process control)
•
In Vivo Predictive (eg: QbD purposes: CMA, CPP, CQA assessment; not
necessarily Fast or Cheap)
Need to “take into account” buffer, buffer capacity, drug pKa, drug solubility, pH,
pH changes, hydrodynamics, absorption, etc
•
Need to consider BCS Class in selecting appropriate dissolution
methodologies from several options
• Current compendial methods (eg: Apparatus I, II, IV)
• Multicompartment systems: Gastrointestinal Simulators (eg: GIS, ASD)
• Multiphase systems: (eg: Biphasic)
Need to “take into account” drug pKa (acid(a), base (b), neutral (c)), solubility,
buffer, buffer capacity, pH, pH changes, absorption, etc.
26
Acknowledgements
•
•
•
Brian J. Krieg
Deanna Mudie
Gordon Amidon
Graduate Student,
Postdoctoral Fellow
Co-advisor
Financial Support Provided by:
• Chingju Wang Sheu Graduate Student Fellowship: 2009-2011
• USP Fellowship: 2010-2012
• AstraZeneca (Bertil Abrahamson, Jennifer Sheng) 2012-2013
• FDA Contract HHSF223201310144C: 2013-2016
27
References:
1.
2.
3.
4.
5.
6.
7.
8.
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