DISSOLUTION RATE LIMITING AUC: SIMPLE ......DISSOLUTION RATE LIMITING AUC: SIMPLE METHODOLOGY FOR MEASURING DISSOLUTION RATE OF THE ENTIRE DOSE IN BIORELEVANT MEDIA Jesse Kuiper and

DISSOLUTION RATE LIMITING AUC: SIMPLE METHODOLOGY FOR MEASURING DISSOLUTION RATE OF THE ENTIRE DOSE IN BIORELEVANT MEDIA

Jesse Kuiper and Paul Harmon

Outline2

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

Outline3




Conclusions

Formulation-Based Absorption: Any Solid Oral Dosage Form

4

GI Tract

(The MiMBA View…)

tabletgranules API Particles (10-50 um)

DissolvedDrug molecules

Dissolution Rate (of API Particle) ~ (Particle SA)*(Diffusion Term)*(Cs – Cl)

lumen

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…

flux drug absorbed = A membrane * [drug lumen] * K permeability

4

Dissolution Rate Limited AUC5

API Particles


lumen

1

2

• 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.

• 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)

• 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?

How to Measure Aggregate Flux –Whole Dose Must Dissolve

6

API Particles


lumen

1

2sink

• 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

• How can this be measured? Mimic the system! Put 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)

• 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

Outline7




Conclusions

Understanding 1X Dissolution in Terms of Single Particle Dissolution

8

= 3 ∙ ∙

Amidon, Lenneräs, Shah and Crinson, Pharm. Res. Vol. 12, No. 3, 1995

02468

101214161820

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Con

cent

ratio

n

Single Particle Prediction vs 1x Dissolution

Single ParticlePredictionSolubility Limit

1x Disso

Description of the dissolution of a single particle at infinite dilution

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

Particle (of API) Dissolution Modeling –Dissolution Rates at “1X” Solubility

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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..m = masst = timeD = diffusion coefficientδ = diff. layer thickness (fn. size)

)( bs CCADdtdm −=

δ

Cs

Cb

δ

diffusionlayer

bulksolution

A = surface areaCs = conc in stagnant layerCb = conc in bulk solution

API particle

Theoretical Example: Working at 5 μg/ml Solubility Limit (Calculated)

API particlesize

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?

SA/V ratio = 1/r

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2.5 mg in 500 mL

Dissolution at Dose Relevant Concentrations

The dissolution experiment loses resolution (cannot differentiate between particle sizes)

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API particlesize

Example -If dose is 100 mg, in 500 ml Fassif= 200 ug/ml = 40X sol. limit

(CS-CLIM) approaches 0 rapidly

Practically, What Working at “1X” Means12

Using the 5 μg/mL solubility in FaSSIF example, and the 100 mg dose

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

That’s a lot of FaSSIF!

1X Dissolution is Readily Modeled

APIs pre-dispersed prior to putting in FaSSIF - drug added at 1 mg/ml

why slower rate at end?

13

If API is dispersed properly and that PSD put into the disso calculation –calc/experiment agree well

This Approach Allows Quantitative Comparisons Across Formulation Types

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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 additionaldissolution rate slowing (increase in ρterm (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 withvery fast granule dissolution will approach dispersed API dissolution rate.

Representative 1X Data Comparing Formulation Components

API calculated

WG granulewith surfactant

RC granule

Tablet

dispersed API

optimize

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Outline16




Conclusions

Introduction of the Dosage Form17

2-Stage Dissolution First stage preps the dose form (like the stomach),

portion to the second stage

SGF

FaSSIF

2x FaSSIF, pH Adjusted

Example BC Study –Low Solubility API, all Formulations Amorphous SD

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…

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[TARGET] in FaSSIF is

1200 μg/mL

0

10

20

30

40

50

60

70

80

0 20 40 60 80 100 120 140 160

ug/m

L (p

ost

80K

)

time (min)

Drug C Formulation 1 vs Formulation 3 at Dose Relevant Concentration - 2 Stage Biorelevant dissolution

Formulation 3

Formulation 1

SGF FaSSIF

• Biorelevantdissolution at dose relevant concentration informed animal study

• Formulation 1 and Formulation 3 bracket expected range of dissolution behavior

Clinical Dosage Forms

Formulations Appear Equivalent by Typical Biorelevant Dissolution Methodology and Animal pK Studies

Drug C –Apparent amorphous solubility

at that time...thought all 3 amorphous formulations would be similar..

19

Formulation 1

Formulation 2

Formulation 3

Formulation 4

~10X difference in CMAX

Example 2 – Human AUC BC Study #1 (high dose)20

Something is happening with these enabled formulations beyond solubility enhancement!

Recall the Formulation 1 system –VA-64, SLS, API…

0

10

20

30

40

50

60

70

80

90 fraction of dose sub - 1 micron

What happens to the SDI particles upon exit of the VA-64?

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

Formulations are dissolved in SGF at dose relevant Concentrations (2.4 mg/mL)

Revisit Formulation – How Does it Behave in solution?Speciation: formulations gives different populations of Sub 1μm Particles after SGF stage.

Formulation 180%

Formulation 220%

Formulation 3< 5%

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1-200 micron particles by Malvern Mastersizer, looking at SDI’s alone post SGF stage at 2.4 mg/ml Drug A level

Formulation 1 Gives Large Population of Sub 1μm Particles (in-situ Particle Size Reduction)

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

Particle Size Distribution

0.01 0.1 1 10 100 1000 3000 Particle S ize (µm)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

6.5

7

7.5

8

8.5

9

9.5

10

10.5

11

11.5

Volu

me

(%)

20% of formulation 1 PSD ~10um

Formulation 3 mean PSD ~40 um

80% of Formulation 2 mean PSD ~20 um

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So how do we “do” Biorelevant Dissolution in this case?

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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

0

5

10

15

20

25

30

35

40

45

50

0 10 20 30 40 50 60 70

ug/m

L

Time (min)

Drug C – Formulations 1-3: 1x Sink dissolution vs Simulated

Formulation 1 - Measured



24

Now formulations look very different!

1x Sink Biorelevant Dissolution – Clearly Differentiates Formulations 1-3

Formulation 1 – very rapid rate to sol. limit

Formulation 3 – very slow rate to sol. limit

24

Particle size distributions for previous slide used in simulated dissolution

SDI Below 1 μm

Above 1 μm

Formulation 1 (30% Drug C, 64.25% VA-64, 5% SLS, 0.75% AO)

80% of particles100-1000 nm

20% of particles~10 μm (vol. mean)

Formulation 2 (33% Drug C, 65.5% VA-64, 0.5% AO)

20% of particles100-500 nm

80% of particles~20 μm (vol. mean)

Formulation 3 (99.5% Drug C 0.5% AO)

0% 100%~40 μm (vol. mean)

Dissolution Rates Readily Modeled

0

5

10

15

20

25

30

35

40

45

50

0 10 20 30 40 50 60 70 80 90 100 110 120 130

ug

/mL

dis

solv

ed

time (min)

Simulated Dissolution Curves - Based Upon Measured PSD

Formulation 1

Formulation 2

Formulation 3

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Dissolution rate is an indicator of pK performance

Comparison - Data vs Simulations

0

5

10

15

20

25

30

35

40

45

50

0 10 20 30 40 50 60 70 80

ug/m

L

Time (min)

Drug C – Formulations 1-3: 1x Sink dissolution vs Simulated

Formulation 1 - MeasuredFormulation 2 - MeasuredFormulation 3 - MeasuredFormulation 1 - SimulatedFormulation 2 - SimulatedFormulation 3 - Simulated

In-situ particle size dominates dissolution behavior for dispersions of Drug C

26

Outline27




Conclusions

Summary and Conclusions28

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

Paul Harmon Wei Xu Michael Socki Adam Socia Kendra Galipeau Melanie Marota Justin Moser Leah Buhler

Allen Templeton Mark Mowery

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Documents

DISSOLUTION RATE LIMITING AUC: SIMPLE ......DISSOLUTION RATE LIMITING AUC: SIMPLE METHODOLOGY FOR MEASURING DISSOLUTION RATE OF THE ENTIRE DOSE IN BIORELEVANT MEDIA Jesse Kuiper and