Biorelevant dissolution measurements and

modeling at the drug solubility limit:

Optimizing Exposure Rankings

Nov. 14, 2016

Dr. Paul A. Harmon, Merck & Co. Inc.

• Many of Drug candidates are BCS II/IV

– low solubility, low (IV) to high permeability (II)

– dissolution rate limited absorption fairly common

• Pharma’s challenges

– can we predict relative bioavailability of different formulations of

same BCS II/IV drug? (composition, API particle size distribution)

– do we understand how our formulation composition/ processes

impact the BR dissolution rate (and hence AUC)?

– need a simple biorelevant dissolution methodology, sensitive to

particle size distributions/ “effective” dissolution rate, in which the

majority of the dose can dissolve during the measurement.

– want to avoid two-phase dissolution; or complex many component

systems mimicking stomach/GI (TNO TIM etc.)

2

Optimizing Bioavailability – optimize BR disso rate

Outline

3

• Background: GI tract, low solubility particles dissolving. “MIMBA”

concepts around the BCS system

• The problem: QC dissolution, and typical biorelevant dissolution using

the whole dosage form in 500-900 mls

• The solution. Dispersed API particle dissolution models work (DDD+).

Very sensitive to particle size if you keep drug at or below the

solubility limit in BR media (1X). Introduce only a “fraction” of dosage

form to BR media to get to solubility limit. This provides “the

Yardstick” to optimize your formulation dissolution rates.

• formulation examples of “1X” methodology and clinical outcomes

Formulation-Based Absorption: Conventional

Formulation with Crystalline Drug

4

Disintegration Solubilization

Absorption of dissolved drugGI Tract

(slightly simplified view…)

tabletgranules API crystalline

Particles (10-50 um)

Dissolved

Drug

molecules

lumen

hope

no

particles

exit!

API particle dissolution rate

This problem has been treated in the literature with some reasonable assumptions..

Absorption rate

-dissolution rate limited absorption – drug remains below solubiltiy limit

(Note here it is assumed that majority of

dose is NOT soluble in the stomach)

“MiMBA”: Microscopic Mass Balance Approach

5

Assumptions:• single size, spherical API particles

• particles are dispersed (no aggregation)

• transit time of particles is 3 hours

• tube-human GI SA,length

• plug flow (complete radial mixing)

• assume steady state

abs.

“Estimating the Fraction Dose Absorbed from Suspensions of Poorly Soluble Compounds in Humans: A Mathematical Model” D.

Oh; R. L. Curl; G. L. Amidon; Pharmaceutical Research V10, No 264-270

set up differential equations

with 3 dimentionless

parameters (Dn, Do, An)

[C*]

z

ro

r*

𝑑𝑟∗

𝑑𝑧∗=

−𝐷𝑛

3

(1−𝐶∗)

𝑟∗

𝑑𝐶 ∗

𝑑𝑧 ∗=𝐷𝑛 𝐷𝑜 𝑟 ∗ 1 − 𝐶 ∗ − 2𝐴𝑛 𝐶 ∗

1

This system of 2 differential equations is numerically solved for 3 different

values of An. r* at end of tube is then calculated, which gives mass absorbed.

The Three Dimensionless Parameters

• if ro = 5 um, with 10 ug/ml solubility, disso time = 50 min; D# =3.6

• if ro = 25 um, with 10 ug/ml solubility, disso time =1250 min; D# = 0.12

𝐴𝑛 =𝑟𝑎𝑑𝑖𝑎𝑙 𝑎𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒

𝑎𝑥𝑖𝑎𝑙 𝑐𝑜𝑛𝑣𝑒𝑛𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒~ 𝑃𝑒𝑓𝑓 (𝑙𝑜𝑤,𝑚𝑜𝑑𝑒𝑟𝑎𝑡𝑒, ℎ𝑖𝑔ℎ 𝑝𝑒𝑟𝑚𝑒𝑎𝑏𝑖𝑙. )

𝐷𝑜 =𝐷𝑜𝑠𝑒 𝑖𝑛 𝑚𝑔

𝑑𝑟𝑢𝑔 𝑠𝑜𝑙𝑢𝑏𝑖𝑙𝑖𝑦𝑡𝑚𝑔

𝑚𝑙×250𝑚𝐿 𝑓𝑙𝑢𝑖𝑑 (𝐹𝑎𝑆𝑆𝐼𝐹)

Absorption #

Dose #

Dissolution # 𝐷𝑛 =𝐺𝐼 𝑟𝑒𝑠𝑖𝑑𝑒𝑛𝑐𝑒 𝑡𝑖𝑚𝑒 (3 ℎ𝑜𝑢𝑟𝑠 𝑜𝑟 180 𝑚𝑖𝑛)

𝑝𝑎𝑟𝑡𝑐𝑖𝑙𝑒 𝑑𝑖𝑠𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 𝑡𝑖𝑚𝑒 𝑎𝑡 𝑖𝑛𝑓𝑖𝑛𝑖𝑡𝑒 𝑑𝑖𝑙𝑢𝑡𝑖𝑜𝑛

An =0.6, 1.3 (metoprolol, moderate), 8.5

related to number of particles in tube. Low soluble compound

has high dose number = many particles..

𝑟𝑜2𝑝

3𝐷𝐶𝑠= (Cs=saturated solubility

value)

Fraction Dose Absorbed for An = 1.0; 3-D; as a function

of Do and Dn. Collapse to 2-D...

7

PMF Bioavailability

= F (Fraction Dose Absorbed)

• Maximum F is 86% with An=1

• F increases to 100% when An >1

High F can be achieved with

• High dissolution #

• Low dose #

fast dissolution

All you need to compare formulations is the effective “dissolution number”...

of the formulation in GI fluids...

MiMBA highlights role of API particle size in

optimizing AUC ...

• Dissolution # depends only on API size and solubility in

Fassif. (real situation much worse. API PSD distributions,

we make granules, API may not be dispersed..)

• Pharmaceutical Scientists do not readily have simple

benchtop dissolution methods which are sensitive to API

particle sizes/distributions –in biorelevent media.

• Two phase dissolution? Membranes? TNO TIM? Need

simple “biorelvent dissolution” type methods which clearly

demonstrate API size sensitivity...

8

-consider the two types of dissolution measurements most commonly done

Outline

9

• Background: GI tract, low solubility particles dissolving. “MIMBA”

concepts around the BCS system

• The problem: QC dissolution, and typical biorelevant dissolution using

the whole dosage form in 500-900 mls

• The solution. Dispersed API particle dissolution models work (DDD+).

Very sensitive to particle size if you keep drug at or below the

solubility limit in BR media (1X). Introduce only a “fraction” of dosage

form to BR media to get to solubility limit. This provides “the

Yardstick” to optimize your formulation dissolution rates.

• formulation examples of “1X” methodology and clinical outcomes

“QC” (Quality Control) Dissolution

• QC dissolution media has 3-10X solubilizing power

– Whole tablet/capsule in 900 mL volume

– 100 mg dose then needs 0.3-1.0 mg/ml solubility

– High levels of surfactant added for low soluble MK

– API solubility in GI fluids (Fassif) is much less

• Two limitations of QC dissolution:

– No meaningful dissolution # can be derived from the QC

experiment

– High surfactant levels can microscopically disperse the API particles

in the formulation, an effect that might not happen in biorelevant

media.

Require Dissolution in Biorelevent Media for MiMBA

correlations

“Traditional” Bio-Relevant Dissolution

11

Stomach

Intestine

In-vivo In-vitro models

30min in 250mL SGF Add 2X FaSSIF + NaOH

120min in FaSSIF

Two-stage model

500mL FaSSIF

(pH 6.5)

250mL SGF

(pH 1.8)

..however, big problem here!

tablet

• Simulated gastric fluid (SGF): 250mL

• Simulated fasted small intestinal fluid (FaSSIF): 500mL, 0.2% surfactants

• Two stage model: 250mL SGF 500mL FaSSIF

• Whole dosage form (tablet/capsule)

tablet

Limitations of Traditional Biorelevant Dissolution

• Often only small portion of the dose can dissolve in 500

ml Fassif

– for a 100 mg dose, 20 ug/ml (fassif) solubility MK only

10% of dose can dissolve.

– Dissolution profile dominated by smallest portion of

API PSD, remainder of PSD not probed

– cannot derive a MiMBA type dissolution #

12

% d

ose d

iss.10

time

how discriminating is this?

(between formulations)

(between different size API?)

Not getting information on how

the API distribution can resupply

drug in presence of significant

absorption

Outline

13

• Background: GI tract, low solubility particles dissolving. “MIMBA”

concepts around the BCS system

• The problem: QC dissolution, and typical biorelevant dissolution using

the whole dosage form in 500-900 mls

• The solution. Dispersed API particle dissolution models work (DDD+).

Very sensitive to particle size if you keep drug at or below the

solubility limit in BR media (1X). Introduce only a “fraction” of dosage

form to BR media to get to solubility limit. This provides “the

Yardstick” to optimize your formulation dissolution rates.

• formulation examples of “1X” methodology and clinical outcomes

API dissolution modeling – handles full PSD and

saturation of bulk fluid. Assumes dispersed particles

• Model based on drug particle and the

external mass transfer out from the

unstirred water later (DDD Plus)

• 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..

14

m = masst = timeD = diffusion coefficient

d = diff. layer thickness (fn.

size)

)( bs CCAD

dt

dm

d

Cs

Cb

d

diffusion

layer

bulk

solution

A = surface area

Cs = conc in stagnant layer

Cb = conc in bulk solution

API

particle

drug at sol. limit

calculated profiles: working at 10 ug/ml drug,

drug solubility = 10 ug/ml (1X); monotonic PSD:

15

API

diam.

THIS IS THE “method” to use to be sensitive to API PSD!

Real 7 and 13 um PSD’s (D50) are very hard to tell apart

if you work (for example) at 10X solubility limit

16

Dissolution at “1X” obviates “two phase” disso –whole dose can dissolve in BR

0

1

2

3

4

5

6

7

8

9

10

0 20 40 60 80 100 120

ug

/ml

Time (min)

10x dissolution (100 µg/ml)

0

2

4

6

8

10

0 20 40 60 80 100 120

ug

/ml

Time (min)

1x dissolution (10 µg/ml)

Example: Merck API 1, two lots

17

PSD for lots 28 and 29

Calculated API “1X” Dissolution Profiles

18

solubility in fassif = 11 ug/ml

solubility limit

Merck API 1-pre dispersed/sonicated in SLS then placed into Fassif –

calculated=measured. Numerous API’s fit well if API dispersed well!

19

allows for (conventional) formulation optimization

YARDSTICK!

solubility limit

1X=11 ug/ml

General Solution (1X Biorelevant Dissolution Concept)

1. Obtain API full PSD 2. Measure API solubility in

biorelevant medium

(FaSSIF)

3. Calculate the expected

dissolution (assume the

API is fully dispersed)

4. Perform the biorelevant dissolution at solubility

limit (“1X”) in FaSSIF using

larger dilution

(SGF)

portion of the tablet/granule

tablet

5. Compare dissolution of

formulation (measured) to

API (calculated)

API

(yard stick)

PMFPMF optimization

API PSD reduction

(at sol. limit)

slope –MiMBA D#!

API “1X” dissolution, BR media, as Yardstick

21

API calculated

WG granule

with surfactant

RC granule

(portion of)

tablet

-note, “QC” disso method might be fast for tablets; much higher solubility

dispersed API

optimize

(Fassif or SGF media) YARDSTICK

conceptual data here

• Goal is to drive formulated product disso rate to the calculated

dispersed particle API dissolution curve!

Outline

22

• Background: GI tract, low solubility particles dissolving. “MIMBA”

concepts around the BCS system

• The problem: QC dissolution, and typical biorelevant dissolution using

the whole dosage form in 500-900 mls

• The solution. Dispersed API particle dissolution models work (DDD+).

Very sensitive to particle size if you keep drug at or below the

solubility limit in BR media (1X). Introduce only a “fraction” of dosage

form to BR media to get to solubility limit. This provides “the

Yardstick” to optimize your formulation dissolution rates.

• formulation examples of “1X” methodology and clinical outcomes

OSF Outperforms the Same powder in Tablet

Dose Formulation AUC Cmax GMR GMR

(mg) (0-24hr) AUC Cmax

50 tablet 720 65 0.4 0.33

50 OSF 1750 200

23

• will the “1X” methodology pick up dissolution rate

differences (Dn differences) between the suspended

solids, and the solids compressed into tablet?

(disintegration time is fast and not limiting).

TabletOSF: suspension

Use SGF stage to uniformly disperse tablet in-

solubles, take portion for dilution to “1X” in Fassif

24

SGF –solids stirring

including API

particles/granules

Fassif

ex. take 5.0 mls

-you must prove you obtain appropriate mg of active

-can use whatever size, volume, stir, etc for SGF “stage”

dilute to large vol

Fassif to get to sol.

limit.

At 1X drug

solubility in

fassif

Tablet vs. OSF 1st stage dose relevant in SGF, 2nd stage

at 1x sink in FaSSIF

25

150

SGF

1X dissolution rates predict relative Human AUC differencesd

isso

lve

d

Example BC Study – Low Solubility API, all

Formulations based on Amorphous SD drug

– Formulation 1: 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 that time, “1X” biorelevant dissolution was not a common practice…

26

[TARGET] in

FaSSIF is

1200 mg/mL

0

10

20

30

40

50

60

70

80

0 20 40 60 80 100 120 140 160

ug

/mL

(p

ost

80K

)

time (min)

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

Formulation3Formulation1

SGF FaSSIF

• Biorelevant

dissolution 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

Drug C –

Apparent

amorphous

solubility

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

27

(only ~2-10% of dose

can dissolve)

Formulation 1

Formulation 2

Formulation 3

~10X difference in CMAX

Human AUC BC Study -5X range!

28

Apply “1X” BR dissolution concept

• Place formulations into SGF at dose relevant concentrations (100 -600 mg drug, for example) - but then dilute portion to “1X” solubility limit in fassif (50 ug/ml)

• Absorption can occur in small intestinal (FaSSIF)

29

-dilution could be 2-1000X depending on drug solubility

SGF fassif

1st stage of dissolution

at dose relevant

concentration (1 unit of

100 mg tablet in 250

mls SGF)

DILUTE a portion of

sample (8X) into

FaSSIF at the

amorphous solubility

limit (“1X”)

8X dilution (100 mg tab)48 X dilution (600 mg dose)

Measure the relative

dissolution rates for all

3 formulations

0

5

10

15

20

25

30

35

40

45

50

0 10 20 30 40 50 60 70

ug

/mL

Time (min)

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

Formulation 1 - Measured

Formulation 2 - Measured

Formulation 3 - Measured

30

Now formulations look very different!

Formulation 1 – very rapid rate to sol. limit

Formulation 3 –

very slow rate to

sol. limit

30

1 X Biorelavent dissolution –ranks formulations very well with

human AUC (only Fassif stage shown)

in Fassif post SGF transfer

why/how formulation 1 different? Drug nanoparticles

form from the amorphous solid dispersion # 1 in SGF!

31

How?? See Harmon et al. Molecular Pharmaceutics, 2016, 13,1467-1481

Summary

• If a large fraction of dose remains undissolved in 250 mls

SGF ..

• then this simple, “1X” (working at solubility limit) dissolution

in Fassif offers a relatively simple way to distinguish

dissolution rate differences related to API size, dispersion of

your API in your formulation. SGF-allows dilution to 1X.

• Formulations can be optimized and compared quantitatively

to the “yardstick”—the calculated (dispersed) API 1X profile.

• Relative Human AUC might be predicted –IF the AUC is

humans is dissolution rate limited. That is something we

don’t seem to know ahead of time for sure…

32

Acknowledgements

• Merck & Co. Inc.

• Analytical Sciences:

– Mike Socki, Jesse Kuiper, Kendra Galipeau, Adam Socia

• Biopharmaceutics:

– Filippos Kesisoglou

• Formulation/Preformulation

– Wei Xu, Justin Moser, Pete Wuelfing

33

Questions

Dr. Harmon’s current contact information:

PhaRxmon Consulting, LLC

P.O. Box 300, Eagleville PA 19408

610 212 9817

www.Pharxmonconsulting.com