DISSOLUTION RATE LIMITING AUC: SIMPLE METHODOLOGY FOR ...
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
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
