Renaissance in Dissolution:

Ensuring Product Therapeutic

Performance (Product Interchangeability: Pioneer and Multi-source)

Gordon L Amidon

Charles Walgreen Jr Professor

College of Pharmacy

University of Michigan

Ann Arbor, MI 48109

OrBiTo Meeting 7-1-15, Paris

Gastrointestinal Dissolutions

Initial Volume=250ml

In Vivo Intestinal Volume= 35-70ml

GIS/ASD

Dissolution & Disintegration:

1950’s

Bioperformance Dissolution Technology?

New BCS Guidance: (Revised,

5/2015)

• pH =1-6.8

• Fabs=85%

• BCS Class III – Qualitatively Same

– Quantitatively

Similar

The Science of Bioequivalence (BE)

is at the Absorption Site

0

M(t)

t

w w

A w

w w w

P C dAdt

j P C

The New Product Science:

Clinical

• Patient Receives

Product

• -Not Drug

• Product=Labeling

Bioequivalence (BE) is

Product Science

0

M(t)

t

w w

A w

w w w

P C dAdt

j P C

Need a Renaissance

Disintegration Apparatus

Dissolution 1970’s

Gastrointestinal Volumes?

USP Volume= 35-70ml

Solid Drug Solid Drug <= Solid Drug <=

2mm

Disintegrated

Drug

Dissolved

Drug

Stomach

Liquid

Vol

Solid Drug Solid Drug <= Solid Drug <=

2mm

Disintegrated

Drug

Dissolved

Drug

Intestine Liquid

Vol

Solid Drug Solid Drug <= Solid Drug <=

2mm

Disintegrated

Drug

Dissolved

Drug

Solid Drug Solid Drug <= Solid Drug <=

2mm

Disintegrated

Drug

Dissolved

Drug

pH

pH

Oral Dose Oral Liquid

disintegration disintegration dissolution

disintegration disintegration dissolution

disintegration disintegration dissolution

disintegration disintegration dissolution

absorption

absorption

absorption

gastric

secretion

absorption

Ph

ase III On

ly

Ph

ase III On

ly

Int0

In

t1 I

nt2

In

t5 I

nt6

In

t3 I

nt4

van Helmont, J. B., Oriatrike or Physick Refined, transl. J. Chandler, London,

1662

Beaumont, W., Experiments and Ovservations on the Gastric Juice and the

Physiology of Digestion, Plattsburg, Va. 1833

GI 1830: William Beaumont

UM Drug Regulatory Science

• Local GI Drug, Melamine (Duxin Sun &

– G L Amidon)

• Fluid Mechanics, Intestinal & Plasma

Sampling, GIS/ASD Dissolution

– G L Amidon, G E Amidon, Duxin Sun

Intubation Procedure in Human GI Tract*

Port Locations:

1. Stomach

2. Duodenum

3. Jejunum

4. Upper Ileum

Fluoroscopic photo of GI tube placement.

Shown are 3 aspiration ports located in the

stomach, proximal jejunum, and distal jejunum.

1

4

3

2

*Courtesy: Duxin Sun, University of Michigan

SMALL INTESTINE: Motility

Motility

Motility

probes

Cross-section

4.8 mm (o.d.)

Gastric Manometry:

GASTRIC EMPTYING STUDY (1998)

Stomach & Small Intestine Motility

Motility

Gastric Emptying: Motility

Phase*

*R.L. Oberle, T.S. Chen, C. Lloyd, G.L. Amidon, J.L. Barnett, C. Owyang and J.H. Meyer,

The influence of the interdigestive migrating myoelectric complex on the gastric emptying

of liquids, Gastroenterology, 99, 1275 (1990).

Profile of drug markers for 0.7 mm CAFF and 3.6 mm APAP pellets

overlaid on corresponding antral motility with designated tInitial

time points at 4000 cP viscous caloric meal.

GASTRIC EMPTYING STUDY

J.K. Rhie, Y. Hayashi, L.S. Welage, J. Frens, R.J. Wald, J.L. Barnett, G.E. Amidon, L.

Putcha and G.L. Amidon, Drug marker absorption in relation to pellet size, gastric motility

and viscous meals in humans, Pharm.Res., 15, 233 (1998).

Intubation Procedure in Human GI Tract*

Port Locations:

1. Stomach

2. Duodenum

3. Jejunum

4. Upper Ileum

Fluoroscopic photo of GI tube placement.

Shown are 3 aspiration ports located in the

stomach, proximal jejunum, and distal jejunum.

1

4

3

2

*Courtesy: Duxin Sun, University of Michigan

Stomach & Small Intestine Motility

Motility

Motility Subject 3

Gaussian Processes &Phase Detection

(Signal Analysis) Estimating pressure function, f(t). Given a time point t, what is the likely pressure ?

Phase III pressure is consistently high (red).

Phase II oscillates between high and low.

Phase I has very little activity.

Delayed Gastric Emptying* • Fasted state

• Phase-dependent emptying rate & lag time

• Based on experimental results from Oberle et al., 1990

Oberle, R. L.; Chen, T. S.; Lloyd, C.; Barnett, J. L.; Owyang, C.;

Meyer, J.; Amidon, G. L. Gastroenterology 1990, 99, 1275-1282.

* Arjang Talattof (Fourier Series Analysis)

Model Validation:

Volumetric Emptying and Residence

Times

Mudie, D. M.; Murray, K.; Hoad, C. L.;

Pritchard, S. E.; Garnett, M. C.; Amidon,

G. L.; Gowland, P. A.; Spiller, R. C.;

Amidon, G. E.; Marciani, L. Molecular

pharmaceutics 2014, 11, 3039-47.

Davis, S. S.; Hardy, J. G.; Fara, J. W. Gut 1986, 27,

886-92.

p = 0.79

BE: BCS Class III Location-

Dependent Permeation

Dissolution: Where is Science to go? (One Example)

Stomach

10mM

4-21mM

avg

15mM

30mM

70mM

Human GI Bicarbonate

CO2 Partial Pressure Duodenum ~>200 mmHg

(20-30%)

Jejunum->colon: 5-20%

Atmosphere: pCO2=0.03%

High Solubility Drug

• Vs = Volume of Solution

<250 ml,

• pH=1-7.5 (6.8)

• Highest Dose Strength

• Do=Dose/250/C s <1

FDA Glass of Water= 8 oz.

(240 ml)

MRI Images*

• A= Stomach after 240 ml drink

• B= Abdomen

• C= Small bowel water pockets

A B C

Liver

Stomach

Spleen

Spine

Duodenum

Jejunum

Ileum

Liver

Duodenum

Jejunum

Ileum

*Marciani,L., Mol. Pharmaceutics 2014

(submitted)

GI Volumes

• MRI Study*: Gastrointestinal Volumes following 8 oz

(240) ml of water

*Marciani, L., Mol. Pharmaceutics 2014 (Molecular Pharmaceutics )

Mean Volume

Stomach Small Intestine

Intestinal Fluid packets

Subject 7 - 1.4 ml in 2 pockets

Subject 11 - 160 ml in 23 pockets

Subject 14 - 21.3 ml in 8 pockets

Number of Water Pockets

Number Small Bowel Pockets

Number by size

Volume of Water Pockets

Mean Volume of SI Pockets

Volume by Pocket Size

Intestinal Fluid packets

BCS Subclasses

BCS Subclass: Absorption

Profile

• A= Acid

• B= Base

• C= Neutral

BCS SubClasses

BCS Class 0.1 N HCl pH 6.5 Permeability Media*

I High High High PIB**

IIa Low High High 15 and 30 min in PGB** then PIB**

IIb*** High Low High 15 or 30 min in PGB** , then PIB**

IIc Low Low High Dissolution 15 and 30 min in PGB** ,

Then PIB** + surfactant to match in vivo

solubilization

III High High Low Same as I

IVa Low High Low Same as IIa

IVb** High Low Low Same as IIb**

IVc Low Low Low Same as IIc

Gastrointestinal Simulator (GIS)*

ASD=Artificial Stomach Duodenum

S. Takeuchi, (Sawai-Japan) personal communication)

Bicarbonate Buffer: Reactions and Rates

𝑲𝟎 = 𝑯𝟐𝑪𝑶𝟑

𝑪𝑶𝟐 𝒂𝒒

𝑲𝟎 =𝑲𝒉

𝑲𝒅

𝑲𝒉 = ~𝟎. 𝟏 𝒔−𝟏

𝑲𝒅 = ~𝟓𝟎 𝒔−𝟏

𝑲𝟏 = 𝑯 + 𝑯𝑪𝑶𝟑

−

𝑯𝟐𝑪𝑶𝟑

𝑲𝟏 =𝑲𝒇

𝑲𝒓

𝑲𝒇 = 𝟖 × 𝟏𝟎𝟔𝒔−𝟏

𝑲𝒓 = 𝟒. 𝟕 × 𝟏𝟎𝟏𝟎𝒔−𝟏

CO2 𝒂𝒒 + 𝑯𝟐𝑶 ⇌ 𝑯𝟐𝑪𝑶𝟑 ⇌ 𝑯+ + 𝑯𝑪𝑶𝟑−

𝑲𝟎 𝑲𝟏

𝑲𝒂 = 𝑲𝟎 ∙ 𝑲𝟏 = 𝟏𝟎−𝟐.𝟔 ∙ 𝟏𝟎−𝟑.𝟕 𝑯 + 𝑯𝑪𝑶𝟑−

𝑪𝑶𝟐 𝒂𝒒 = 10-6.3

Tablet, HA

Bicarbonate Buffer Physiological

Relevance

• Equilibrium Prevails in

the Bulk (pKa=6.04)

• H2CO3 undergoes a

irreversible (dehydration)

reaction in the Boundary

Layer (BL) due to the

slow (hydration)

– CO2 + H2O reaction

• The irreversible reaction

consumes H+ in the BL

increasing the buffering

effect away from the pKa

𝑪𝑶𝟐 + 𝑯𝟐𝑶 ⇌ 𝑯+ + 𝑯𝑪𝑶𝟑−

GI Lumen

Bulk Solution

HA->H+ + A-

𝐶𝑂2 + 𝐻2𝑂𝑘𝑑 𝐻2𝐶𝑂3 ⇌ 𝐻𝐶𝑂3

− + 𝐻+

BL

Central Hypothesis (CH): New Paradigm of Oral Product Equivalence

CH/A: Oral Generic Product Variability is GI Variability

Hypothesis 1: Oral drug product therapeutic equivalence (same drug, different product

composition, and characteristics/dissolution) is determined by disintegration-dissolution

(release)-absorption (DDA) for the drug (API) in the gastrointestinal tract.

H1A: Oral Drug Product Equivalence is Equivalent Release in the GIT

Hypothesis 2: Equivalent oral product performance (DDA) is confounded by time

dependent gastrointestinal processes: motility/transit, fluid composition secretions, intestinal

permeability.

H2A: Oral Drug Product Variability is Due to GI Variables

Hypothesis 3: Oral Product equivalence would best be determined by in vitro methods

reflecting the GI tract that reflecting the actual variation in GI environment.

H3A: Product Therapeutic Equivalence Best Determined by IPD

Hypothesis 4: Plasma level variation of drug from two products in normal subjects is due to

variation in DDA.

H4A: See H2A

Hypothesis 5: The major variable in the GIT is motility, which can be monitored by

manometry (intubation) or potentially MRI.

H5A: Dosing is random relative to GI motility

Hypothesis 6: Time to GI Phase III is major covariate in oral product plasma variation

Central Hypothesis: New Paradigm of Oral Product Equivalence

CH/A: Oral Generic Product Variability is GI Variability

Hypothesis 1: Oral drug product therapeutic equivalence (same drug, different product

composition, and characteristics/dissolution) is determined by disintegration-dissolution

(release)-absorption (DDA) for the drug (API) in the gastrointestinal tract.

H1A: Oral Drug Product Equivalence is Equivalent Release in the GIT

Hypothesis 2: Equivalent oral product performance (DDA) is confounded by time

dependent gastrointestinal processes: motility/transit, fluid composition secretions, intestinal

permeability.

H2A: Oral Drug Product Variability is Due to GI Variables

Hypothesis 3: Oral Product equivalence would best be determined by in vitro methods

reflecting the GI tract that reflecting the actual variation in GI environment.

H3A: Product Therapeutic Equivalence Best Determined by IPD

Hypothesis 4: Plasma level variation of drug from two products in normal subjects is due to

variation in DDA.

H4A: See H2A

Hypothesis 5: The major variable in the GIT is motility, which can be monitored by

manometry (intubation) or potentially MRI.

H5A: Dosing is random relative to GI motility

Hypothesis 6: Time to GI Phase III is major covariate in oral product plasma variation

Gastrointestinal Simulator (GIS)*

ASD=Artificial Stomach Duodenum

S. Takeuchi, (Sawai-Japan) personal communication)

First Labeling Law: Germany 1516

August 2000 FDA Guidance

G.L. Amidon et. al., Pharmaceutical Research, 12,

413 (1995). (key BCS publication)

Where we are going?

‘Biowaiver”

We CAN NOT waive Bioequivalence

(BE)

Dissolution in What?

?

CO2/Bicarbonate • Bicarbonate Equilibrium

• H2CO3 = HCO3− + H+ Ka1 = 2.5×10−4 ; pKa1 = 3.60 at 25 °C.

•

• HCO3− = CO3

2− + H+ Ka2 = 5.61×10−11 ; pKa2 = 10.33 at 25 °C

•

• Gas Phase Equilibrium

• – CO2(gas) = CO2(dissolved)

•

• where kH=29.76 atm/(mol/L) at 25°C (Henry constant)

•

• CO2(aq) + H2O = H2CO3 (aq)

•

• Then of course we have CO2 transport in the Intestine Transporters, Exchangers, intracellular equilibrium

CO2 + H2O =

H2CO3

CO2

Oral BE

• GI Fluid Volumes

• pH and Bicarbonate/CO2

Pharmaceutical Industry:

• FDA Laws

• 1902: Labeling

• 1938: Safety (Biopharmaceutical)

– Ethylene glycol in IV product

• 1962: Efficacy (Safety)

– Thalidomide

• 1984: Generic Products (Biopharmacetuics)

– Allows reference to an Approved NDA

– Bioequivalence (BE) of primary importance

BE: Dissolution Equipment 2014

• Mainly

quality

control (QC)

• Little In Vivo

Relevance

• Depends on

BCS Class

Renaissance in Dissolution

• In Vivo Processes and in vitro relevance

• Physical Chemistry

• Mass transport and Reaction

– (GIT is complex Chemical Reactor)

• In Vitro Method Development

– (Multiple Methods based on BCS Subclasses)

Validation of LC-MS/MS Method for

Quantification of Mesalamine and Its Metabolite

5-aminosalicylic acid (5ASA) N-acetyl-5-aminosalicylic acid

(AcASA)

N-acetyltransferase I

liver

intestinal mucosa

Internal standard: 4-aminosalicylic acid

• GI fluids were diluted by blank plasma due to limited volume of drug-free GI fluids.

Sample Collection

• GI fluids

– Stomach, duodenum, jejunum, early ileum

– 0.5-1 mL at each port at 1, 2, 3, 4, 5, 6, 7 hours

• Blood

– 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 hours

• Feces

– 0-12, 12-24, 24-48, 48-72, 72-96 hours

-500

0

500

1000

1500

2000

2500

0 10 20 30 40 Con

cen

tra

tion

(n

g/m

L)

Time (hrs)

5ASA Profile in Plasma Solution

Pentasa

Aspriso

Lialda

Apriso

-200

800

1800

2800

3800

4800

5800

0 10 20 30 40

Co

nce

ntr

ati

on

(n

g/m

L)

Time (hrs)

AcASA Profile in Plasma Solution

Pentasa

Aspriso

Lialda

Apriso

Small Bowel Pocket Number and

Size

Bioequivalence Simulations:

BCS Class I

Bioequivalence Simulations:

BCS Class III Constant Permeation