DISSOLUTION RATE LIMITING AUC:
SIMPLE METHODOLOGY FOR
MEASURING DISSOLUTION RATE OF THE
ENTIRE DOSE IN BIORELEVANT MEDIA
Jesse Kuiper and Paul Harmon
Outline
2




Understanding the path to absorption (and the
meaning of dissolution rate controlled absorption)
Understanding the dissolution contribution of the
entire dose – “1X Biorelevant Dissolution”
Application of “1X Biorelevant Dissolution” concept
– An in-depth case study
Conclusions
Outline
3




Understanding the path to absorption (and the
meaning of dissolution rate controlled absorption)
Understanding the dissolution contribution of the
entire dose – “1X Biorelevant Dissolution”
Application of “1X Biorelevant Dissolution” concept
– An in-depth case study
Conclusions
Formulation-Based Absorption: Any Solid Oral
(The MiMBA View…)
Dosage Form
4
Dissolved
Drug
molecules
tablet
granules
API Particles (10-50 um)
lumen
GI Tract
flux drug absorbed = A membrane * [drug lumen] * K permeability
Dissolution Rate (of API Particle) ~ (Particle SA)*(Diffusion Term)*(Cs – Cl)
Concentration difference term (Cs – Cl) drives dissolution rate. If drug has high
solubility dissolution rates are fast given fixed particle size. If drug has low
solubility, disso rate is slow …particles may come out of “pipe” at end…
4
Dissolution Rate Limited AUC
5
• If 1 > 2, then dissolved drug concentration in the GI
is “pegged” at the solubility limit – this is
solubility/permeability limited exposure. In this
regime, different formulations of same API give
similar AUC.
API Particles
1
Dissolved
Drug
molecules
lumen
• If 2 > 1, then dissolved drug concentration in GI is
below the drug solubility limit, this is dissolution rate
limited (disso rate can’t keep up with permeability
loses). In this regime AUC may be sensitive to
formulation details...(API PSD, for example)
2
• How to measure/compare “aggregate” API particle
dissolution rates – as they dissolve in aggregate (from
different formulations) as this dissolution drives the
[API] in GI fluids to the its solubility limit?
6
How to Measure Aggregate Flux –
Whole Dose Must Dissolve
• In the case where C provides constant sink for
dissolved drug to go, the rate “1” of transition from A
to B matters, regardless of amount dosed, therefore
the dissolution behavior of the entire dose matters
API Particles
• How can this be measured? Mimic the system! Put
1
Dissolved
Drug
molecules
lumen
the dose inside a permeable membrane (only drug
in solution gets through) and have large volume on
other side of membrane to keep [drug] below its
solubility limit or some sort of way to remove drug
outside membrane (inside always driving to sol
limit). Also, biphasic dissolution (aqueous/organic)
2
sink
• Is there a more elegant way? Simply put a portion
of dose into BR media AT the solubility limit,
compare disso profile (rate) to get there!
THIS IS 1X BIORELEVANT DISSOLUITION
Outline
7




Understanding the path to absorption (and the
meaning of dissolution rate controlled absorption)
Understanding the dissolution contribution of the
entire dose – “1X Biorelevant Dissolution”
Application of “1X Biorelevant Dissolution” concept
– An in-depth case study
Conclusions
Understanding 1X Dissolution in Terms
of Single Particle Dissolution
8
=
3∙
∙
Description of the dissolution of a single particle at infinite dilution
Concentration
Single Particle Prediction vs 1x Dissolution
20
18
16
14
12
10
8
6
4
2
0
Single Particle
Prediction
Solubility Limit
1x Disso
For a given population of
homogeneous particle size, 1x sink
Dissolution will initially match the
single particle dissolution rate
predicted by the above equation,
but as the CS term approaches the
solubility limit CS  (CS-CLIM),
therefore the rate slows
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Amidon, Lenneräs, Shah and Crinson, Pharm. Res. Vol. 12, No. 3, 1995
Particle (of API) Dissolution Modeling –
Dissolution Rates at “1X” Solubility
9
diffusion
layer
bulk
solution
API
particle



Cs
dm D
= A(Cs − Cb )
dt δ
δ
m = mass
t = time
D = diffusion coefficient
δ = diff. layer thickness (fn. size)

Cb

Model based on drug particle and the
external mass transfer out from the
unstirred water later (Nernst-Brunner or
Noyes-Whitney)
Assumes solubility limit is quickly reached in
a thin layer around particle – then drug
molecule diffusion out of the unstirred layer
into the bulk soln is the mass transfer rate
limiting step.
need accurate PSD*, solubility value, and
diffusion coefficient of molecule.
smaller PSD means more surface area per
mass, smaller diffusion layer thickness so
dissolution rate goes up!
*PSD under dissolution conditions..
A = surface area
Cs = conc in stagnant layer
Cb = conc in bulk solution
Theoretical Example: Working at 5
μg/ml Solubility Limit (Calculated)
10
2.5 mg
in 500 mL
API
particle
size
SA/V ratio = 1/r
1) This is why smaller API size is better IF disso rate limited!
2) What would happen if this was done at dose relevant concentration?
Dissolution at Dose Relevant
Concentrations
11
API
particle
size
Example If dose is
100 mg, in
500 ml Fassif
= 200 ug/ml
= 40X sol.
limit
(CS-CLIM)
approaches
0 rapidly
The dissolution experiment loses resolution (cannot differentiate
between particle sizes)
Practically, What Working at “1X” Means
12
Using the 5
μg/mL solubility
in FaSSIF
example, and the
100 mg dose
That’s a lot of FaSSIF!
To work at “1X” with a complete 100 mg tablet then
would require a 20,000 mL volume
We work with granules (example here, 1/40th
weight of a tablet in 500 mL faSSIF) or portions of
tablets – or pre-disintegrated in SGF



1X Dissolution is Readily Modeled
13
If API is dispersed properly and that PSD put into the disso
calculation –calc/experiment agree well
why slower rate at end?
APIs pre-dispersed prior to putting in
FaSSIF - drug added at 1 mg/ml
14
This Approach Allows Quantitative
Comparisons Across Formulation Types
Formulation Attribute
1x Dissolution Response
Formulation processes strive to disperse
the API particles to their primary size
from a tablet
Formulations that do this better will have
faster rates of dissolution than those that
do this poorly
Granulation of API
Granulation can help with dispersion of
particles in dissolution – also over
granulation can add additional
dissolution rate slowing (increase in ρ
term (particle density)
Addition of Surfactants
Helping wet the particles may improve
dissolution rate
Understanding the dissolution rate of well dispersed API particles is the first step
in evaluating dissolution performance – as a very well dispersed formulation with
very fast granule dissolution will approach dispersed API dissolution rate.
Representative 1X Data Comparing Formulation
Components
15
API calculated
dispersed API
WG granule
with surfactant
optimize
RC granule
Tablet
Outline
16




Understanding the path to absorption (and the
meaning of dissolution rate controlled absorption)
Understanding the dissolution contribution of the
entire dose – “1X Biorelevant Dissolution”
Application of “1X Biorelevant Dissolution” concept
– An in-depth case study
Conclusions
Introduction of the Dosage Form
17
2x FaSSIF, pH Adjusted
SGF
FaSSIF


2-Stage Dissolution
First stage preps the dose form (like the stomach),
portion to the second stage
Example BC Study –
Low Solubility API, all Formulations Amorphous SD
18

Drug is BCS Class II (poorly soluble, readily absorbed)

Formulation 1 (reference formulation): VA-64 / Drug C / SLS
(65 : 30 : 5) in amorphous SD dispersion intermediate (SDI)

Formulation 2: Removed SLS from dispersion. Potential issues
with crystallization of SLS out of dispersion observed in
Formulation 1 stability studies. Is it really needed IN the
dispersion? Add same SLS to tablet “external” to SDI.

Formulation 3: Removed VA-64 and SLS; just SD amorphous
drug A in the SDI. Combination products need more tablet
volume – is the VA-64 polymer in the dispersion really needed?
Add SLS externally to tablet.
At this time, “1X” biorelevant dissolution was not a common practice…
Formulations Appear Equivalent by Typical Biorelevant
Dissolution Methodology and Animal pK Studies
19
• Biorelevant
dissolution at dose
relevant
concentration
informed animal
study
Drug C Formulation 1 vs Formulation 3 at Dose Relevant
Concentration - 2 Stage Biorelevant dissolution
80
Drug C –
Apparent
amorphous
solubility
SGF
70
FaSSIF
ug/mL (post 80K)
60
50
[TARGET] in
FaSSIF is
1200 μg/mL
40
30
• Formulation 1 and
Formulation 3
bracket expected
range of
dissolution
behavior
20
Formulation 3
10
Formulation 1
0
0
20
40
60
80
time (min)
100
120
140
160
Clinical Dosage Forms
at that time...thought all 3 amorphous formulations would be similar..
Example 2 – Human AUC BC Study #1
(high dose)
20
Formulation 1
Something is happening with these
enabled formulations beyond
solubility enhancement!
~10X difference in CMAX
Formulation 2
Formulation 3
Formulation 4
Recall the Formulation 1 system –
VA-64, SLS, API…
Revisit Formulation – How Does it Behave in solution?
Speciation: formulations gives different populations of Sub 1μm Particles after SGF stage.
21
What happens to the SDI particles upon exit of the VA-64?
90
fraction of dose sub - 1 micron
80
70
60
Formulation 1
80%
Formulations are dissolved in
SGF at dose relevant
Concentrations (2.4 mg/mL)
50
40
30
20
10
Formulation 2
20%
Formulation 3
< 5%
0
End of SGF stage: huge particle size differences!
80% of Formulation 1 is sub - 1 micron; 20% for formulation 2, and formulation 3 is just the 40 um
mean PSD
Formulation 1 Gives Large Population of Sub 1μm Particles
(in-situ Particle Size Reduction)
22
11.5
P article Size Distributio n
11
Formulation 3
mean PSD
~40 um
10.5
10
9.5
9
8.5
8
7.5
Volume (%)
7
6.5
20% of
formulation
1 PSD
~10um
80% of
Formulation 2
mean PSD
~20 um
6
5.5
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
0.01
0.1
1
10
Particle S ize (µm )
100
1000
3000
1-200 micron particles by
Malvern Mastersizer,
looking at SDI’s alone post
SGF stage at 2.4 mg/ml
Drug A level
Formulation1 not only forms
larger amount of sub-micron
particles, but its micron
range particles are smaller
than those measured for
formulations 2 and 3 post
SGF
23
So how do we “do” Biorelevant
Dissolution in this case?




Entire dose influences dissolution – at dose relevant concentrations,
dissolution captures ~5% of dose in solution
Recall, for these formulations, the amorphous dispersion is VA64
The polymer readily dissolves in the stomach (SGF), the speciation
event will happen prior to the region where absorption can occur
So, you do 1st stage of dissolution at dose relevant concentration
(dose/250 mL SGF), then, DILUTE a portion of sample into FaSSIF at
the solubility limit of the drug (“1X”) and measure the relative
dissolution rates
-dilution could be 2-200X depending on amorphous drug solubility
1x Sink Biorelevant Dissolution – Clearly
Differentiates Formulations 1-3
24
Drug C – Formulations 1-3: 1x Sink dissolution vs
Simulated
50
Now formulations look very different!
45
40
Formulation 1 – very rapid rate to sol. limit
35
ug/mL
30
25
20
15
Formulation 3 – very
slow rate to sol. limit
10
5
Formulation 1 - Measured
Formulation 2 - Measured
Formulation 3 - Measured
0
0
10
20
30
40
50
60
70
Time (min)
24
Dissolution Rates Readily Modeled
25
Below 1
μm
Formulation 1
(30% Drug C,
64.25% VA64, 5% SLS,
0.75% AO)
80% of
particles
100-1000 nm
Formulation 2
(33% Drug C,
65.5% VA-64,
0.5% AO)
20% of
particles
100-500 nm
Above 1
μm
Simulated Dissolution Curves - Based Upon Measured PSD
50
45
20% of
particles
~10 μm (vol.
mean)
80% of
particles
~20 μm (vol.
mean)
40
35
ug/mL dissolved
SDI
30
25
20
15
Formulation 1
10
Formulation 3
(99.5% Drug
C 0.5% AO)
0%
100%
~40 μm (vol.
mean)
Formulation 2
Formulation 3
5
0
0
10
20
30
40
50
60
70
80
90
100
110
time (min)
Particle size distributions for previous slide used in simulated dissolution
120
130
Comparison - Data vs Simulations
26
Drug C – Formulations 1-3: 1x Sink dissolution vs Simulated
In-situ particle size dominates
dissolution behavior for
dispersions of Drug C
50
45
40
35
ug/mL
30
25
20
15
Formulation 1 - Measured
Formulation 2 - Measured
10
Formulation 3 - Measured
5
Formulation 1 - Simulated
Formulation 2 - Simulated
0
Formulation 3 - Simulated
0
10
20
30
40
50
60
70
Time (min)
Dissolution rate is an indicator of pK performance
80
Outline
27




Understanding the path to absorption (and the
meaning of dissolution rate controlled absorption)
Understanding the dissolution contribution of the
entire dose – “1X Biorelevant Dissolution”
Application of “1X Biorelevant Dissolution” concept
– An in-depth case study
Conclusions
Summary and Conclusions
28



When dissolution rate is the rate limiting step in
absorption, it is important to understand the effective
dissolution rate of the entire dose
“1X Biorelevant Dissolution” is a discriminating
dissolution method that allows for evaluation of subtle
formulation changes
“1X Biorelevant Dissolution” is a simple yet powerful
tool to predict exposure in animal and human subjects
Acknowledgements
29








Paul Harmon
Wei Xu
Michael Socki
Adam Socia
Kendra Galipeau
Melanie Marota
Justin Moser
Leah Buhler


Allen Templeton
Mark Mowery