Dissolution – where physiochemistry meets biology

PhysChem Forum, 20th Sept 2011Nottingham

Dr Brian Henry

Pharmaceutical Science

Pfizer Global Research and Development

brian.henry@pfizer.com

2

Today’s Talk

Biology

Physiochemistry

3

Drug Absorption

sampling

4

Dosage Form Performance1

DosageForm

Drug inSolution

Blood Site of Action

Therapeutic Effect

PharmacokineticMeasurement

Clinical / PDMeasurement

Gut W

all

Dissolution

Solubility Permeability

1 Based on a slide from 2007 AAPS-FDA BCS, BE, and Beyond Workshop Presentation, entitled General BA/BE Issues, Dale Conner, Division of Bioequivalence, Office of Generic Drugs, CDER, FDA

What is dissolution?

5

Dissolution Testing of Oral Dosage Form

What is Dissolution?

• Dissolution is the rate at which a substance dissolves in a fluid.

• In pharmaceutical practice, dissolution is the rate at which a drug in a dosage form dissolves into the fluid surrounding it.

• In the case of modified release dosage forms dissolution rate and release rate of drug are controlled by the design of drug product

6

Two Very Different Purposes of Dissolution Test

As a quality control measure for dosage form• Batch to batch reproducibility to assure consistency in quality of manufactured product

• Shelf life stability

• Assure manufacturing process changes do not impact performance (typically requires BE study)

To predict dosage form PK performance in vivo• Guide formulation selection, design and scale-up during development

– Quality by design and support regulatory filings

• Help select and set specifications for API form and particle size

• Guide bioequivalence strategy

7

Disintegration and Dissolution

.....

D

D

D

D

D D

8

Dissolution Model

Solid Surface

Cs

C

x=0 x=h

Bulk solution

Diffusion Layer

Noyes and Whitney Equation

)(dM

CCsh

DS

dt

• M: the mass of solute dissolved at time t• dM/dt: the mass rate of dissolution• D: diffusion coefficient of the solute in solution• S: the surface area of the exposed solid• h: the thickness of the diffusion layer• Cs: the solubility of the solid• C: the concentration of solute in the bulk solution and at time t

9

What Factors Influence Dissolution?

The properties of drug• Solubility of the API in the dissolution medium

• Whether the API is hydrophilic or hydrophobic (ease of surface wetting)

• The particle size/shape of the API

• Whether the API is crystalline or amorphous in the drug product

• If there are polymorphs, which polymorph is present

• If a salt form is used

The quality and design of the drug product• The composition of the drug product and how they are added

• Manufacturing processes and steps

• Whether the product is designed to immediately release the API, to delay release, or to release the drug over time.

The condition of dissolution tested

10

USP Dissolution apparatus

USP I/II USP III

USP IV

11

Dissolution of different 250 mg Crizotinib dosage forms

Dissolution for Multiple Crizotinib Dosage Forms in 0.1N HCl

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Time (mins)

% D

isso

lved

PIC pH 1

MST pH 1

ICH pH 1

Note: 75 minutes is an

infinity spin, 15 minutes at 200

RPM

Method conditions: 0.1N HCl, Baskets 100 RPM

12

Crizotinib ‘Powder in Capsule’ vs Tablet BA study

A8081008

Time (hr)

PF

-02

34

10

66

Me

dia

n C

on

cen

tra

tion

0 20 40 60 80 100

05

01

00

15

0250 mg IR TABLET250 mg SD PIC

1313

0

20

40

60

80

100

120

0 1 2 3 4

Time (hour)

% re

leas

ed formulation1

formulation 2

formulation 3

0

0.002

0.004

0.006

0.008

0.01

0.012

0.014

0.016

0.018

0.02

0 5 10 15 20 25 30

Time (hour)P

lasm

a co

nc

(ug

/ml)

formulation 1

formulation 2

formulation 3

Bridging in vitro to in vivo

in vitro performance In vivo performance

How can we ensure the low risk of failing to achieve the desired in vivo performance?

14

In vitro/In vivo correlations (IVIVC) Definition5

Definition

A predictive mathematical treatment describing the relationship between an in vitro property of a dosage form (usually the rate or extent of drug release) and a relevant in vivo response (e.g. drug concentration in plasma or amount of drug absorbed).

… to accurately and precisely predicting expected bioavailability characteristics for an ER product from dissolution profile characteristics …

5 Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/ In Vivo Correlations, September 1997

14

15

Concept of Convolution and DeconvolutionConvolution

The convolution method is a simulation method used to predict the blood/plasma concentration when a drug is administered orally.

Deconvolution

Deconvolution is the process to obtain input function with known plasma concentrations

Deconvolution is the reverse process of convolution

Pharmacokinetic profileDeconvolution

Convolution

1616

IVIVC Model

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Fraction Dissolved

Fabs vs Fdiss 1*100 mg SR 186

Fabs vs Fdiss 2*50 mg SR 190

Fabs vs Fdiss 200 mg A61138

Fabs vs Fdiss 200 mg A61140

Fabs vs Fdiss 200 mg Target

Line of Unity

Regression

Rsq=0.9937 slope=0.884

17

So that’s about it for dissolution, Dinner?

…well, it’s rarely that straight forward

18

The problems with predicting dissolution are very fundamentalConsider what is happening at the primary particle surface

Solid Surface

Cs

C

x=0 x=h

Bulk solution

Diffusion Layer

)(dM

CCsh

DS

dt

Surface area

Particle size distribution

Particle shape

Wetting and aggregation

Bulk solution solubility

pH differences/precipitation

Bile solubilisation

Dissolution vs absorption rates

Unstirred Water layer

pH gradient

Bile micelle migration

Mix hydrodynamics

19

Intrinsic dissolution rate; the simplest form of dissolution testing

• Constant surface area compact (ensure solid form remains intact after compression)

• Rotating disk (or static disk & rotating fluid)– Well defined hydrodynamics

• Detection methodology (on-line or off line)

• Temperature controlled• Means to assess solid form after

experiment

20

Example experimental data for a drug HCl Salt

Data collected ~every 5 seconds

If well behaved, (no change in solid form) linear dissolution is expected

Slope is proportional to dissolution rate

Curvature of concentration profile indicates a phase transformation

0 5 10 15 20 25 300

5

10

15

20

25 RDD of Test Compound 3 at pH2

Co

nce

ntr

atio

n

Time (min)

0.01 N HCl + 0.1 M NaCl + 0.2 M NaCl

21

Delavirdine – NNRTI for the treatment of HIV

1 2 3 4 5 6 7 8

1

10

100

1000

10000

100000

To

tal C

on

cen

tra

tion

of

De

lavi

rdin

e (

µg

/mL

)

pH

Free Base Solubility

Salt SolubilityBasic compound, pKa~4.5

Intrinsic solubility (~1µg/mL)

Salt solubility about 200 mg/mL

Developed as a mesylate salt but has erratic bioavailability

22

Intrinsic Dissolution Rate of Delavirdine Mesylate

Salt very soluble• Should dissolve quickly

• Should be pH independent

As the pH increased, the dissolution rate decreased

Free base precipitation on the compact confirmed by PXRD

1 2 3 4 5 6

Dis

solu

tio

n R

ate

(µg

cm-2se

c-1)

Bulk Solution pH

Calculated salt dissolution rates

Measured disolution rates

23

What is happening?

BH+A-(solid)

BH+(aq)+ H2O

A-(aq)+ H2O

Dissolution Hydrolysis

B(aq)+ H3O+

HA(aq)+ OH-

Precipitation

B(solid)

24

Free base precipitation

25

Impact of Free Base on the dissolution rate of Delavirdine Mesylate at pH 2 dissolutionSmall amount of free base in the compact has a dramatic impact on dissolution

26

Impact of citric acid in the compact on the dissolution rate of Delavirdine Mesylate - Diffusion Layer Modulation

27

Rat Study Results

• Diffusion Layer modification increases oral bioavailability

0 5 10 15 20 250

1

2

3

4

5

6

7

Delavirdine Formulations in Rat with pH 5 Stomach

CA Granules Tablet

De

lavi

rdin

e C

on

cen

tra

tion

(µ

g/m

L)

Time (hr)

28

New technologies to provide a greater understanding of dissolution mechanisms

SDI300 Surface Dissolution Imaging System: A powerful

new tool for formulations optimization

29

The Artificial Stomach Duodenal (ASD) model to investigate the impact of pH change on dissolution

Stomach

Duodenum

GastricFluid

DuodenalFluid

GastricEmpty Pump

DuodenalEmpty Pump

30

Typical ASD dissolution profiles

solid soln

waste

bioavailable

Stomach

Duodenum

solid soln

Formulation

pH 2-4

pH ~6-7

disintegration

dissolutiondissolution

dissolution

liquidtransport

solidtransport

liquidtransportsolid

transport

solubilization

precipitation

precipitation

-20 0 20 40 60 80 100 120 140 160 180 200

Con

cen

tra

tion

Time (min)

Stomach

Duodenum

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In vitro/in vivo correlation for ASD

(Carino, S.R., D.C. Sperry, and M. Hawley, Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model. J. Pharm. Sci., 2006, 95(1), 116-125.)

• Correlation of ASD AUC to in vivo data for carbamazepine polymorphs:

32

Formulations of compound X were being developed for rapid oral onset of action

• Weak based with low solubility >pH4.5 ~10ug/mL

• High solubility at gastric pH (>5mg/mL)

• Three crystalline solid forms were available– Free base

• Intrinsic solubility of 10ug/mL– Citrate salt

• Intrinsic solubility of 20mg/mL– Mesylate salt

• Intrinsic solubility of 80mg/mL

33

ASD data for Compound X solid forms with a pH 4 stomach.

•The mesylate performed poorly in the duodenum with a gastric of pH4.0

•Precipitation to free base?

•The citrate salt performs the best in the duodenum compartment

•Slower dissolution leading to less precipitation at higher pH

Concentration in solution in the Stomach Concentration in solution in the Duodenum

34

pH modulated dog model to monitor oral absorption of Compound X salts from stomachs of low and high pH

Pentagastrin treated dogs• Good precedent for use in dogs to reduce stomach pH• 10mcg/kg im

– 15 minutes prior to dosing and 30 minutes post dosing

Pantoprazole treated dogs• Low hepatic drug interaction potential and used in veterinary

practise with dogs• 1mg/kg iv 12 hours pre dose and 1 hour post dose

Compound X formulated as rapidly disintegrating tablets of the the free base, mesylate and citrate salts

Tablets dose with the Bravo capsule on a fasted stomach with a small volume of water

Medtronic Bravo pH telemetry systems

35

Measurement of the pH of the gastrointestinal tract of male Beagle dogs using Bravo pH telemetry Capsules

Pantoprazole treated Pentagastrin treated

001M

002M

003M

004M

001M

002M

003M

004M

Time (hrs)

pH

0

8

36

Gastric pH in male beagle dogs after the different pretreatments to control Gastric pH

0

1

2

3

4

5

6

7

8

No treatment Pentagastrin Pantoprazole

Treatment

pH

Mean = 1.3 + 0.2

Mean = 6.6 + 0.7Mean = 4.6 + 2.7

37

Comparison of mean maximum plasma concentrations (Cmax) of Compound X following a single oral administration of Compound X free‑base, mesylate and citrate with no medication, pentagastrin medication and pantoprazole

0

100

200

300

400

500

600

700

None Pentagastrin Pantoprazole

Cm

ax (n

g/m

L)

.

Free base Mesylate Citrate

38

Comparison of the mean time (tmax) to reach the maximum plasma concentration of Compound X following a single oral administration of Compound X free-base, mesylate and citrate with no medication, pentagastrin medication and pantoprazole medication

0.00

0.50

1.00

1.50

2.00

2.50

3.00

None Pentagastrin Pantoprazole

tmax (

h)

.

Free base Mesylate Citrate

Pha

se 1

Pha

se 2

Pha

se 3

Pha

se 4

Pha

se 6

Pha

se 8

Pha

se 5

Pha

se 7

Pha

se 9

39

pH modulated dog model to monitor oral absorption of Compound X salts from stomachs of low and high pH

•All Compound X salts performed better at lower stomach pH

• Faster absorption as measured by shorter Tmax and Higher Cmax

•Trend for the citrate salt to have more reliable performance across a wider pH range

•Supported by the ASD in vitro dissolution/precipitation model

•Bravo pH telemetry capsule worked successfully in this dog model

•Drug pre-treatments successfully controlled dog stomach pH to desired level

• Fasted dog stomach highly variable

40

Conventional USP dissolution approaches do not mimic the dynamic conditions of the intralumenal environment

+

≠

(*2 - Picture supplied by Prof. Christos Reppas, National & KapodistrianUniversity of Athens, Greece)

(*2)(*1 - Using models of the human digestive process to simulate the fate of dosage forms, M. Wickham & H. Parry, APS Biopharmaceutics & Drug Delivery Meeting, Dec 07)

(*1)

41

New technologies now provide a view from the tablets perspective

Daniel Bar-Shalom

Faculty of Pharmaceutical Sciences University of Copenhagen

42

What is really happening in the GI tract?

DOG 05AA7

05

10152025303540

0 45 90 135

180

225

270

315

360

405

450

495

540

585

630

time (mins)

pH

Temp

Pressure

New technologies now provide a view from the Tablets perspective

43

Typical daily variation in gastric pH in a health subject

44

Reduced acid secretion in the Stomach Hypochlorhydria and Achlorhydria

Disease states know to be associated with reduced acid production• Malnutrition• HIV/AIDs• Gastric infections (incl H Pylori)• Gastric inflammation and cancer• Autoimmune diseases (pernicious anaemia, thyroid disorders)• Genetic Disorders

Surgical induced hypochlorhydria• Gastric resection, Vagotomy

Drug induced hypochlorhydria• H2 antagonists, Proton Pump Inhibitors, Antacids• Cannabis• Aspirin, alcohol

Aged associated hypochlorhydria

45

Gastritis and Acid Secretion in the Elderly

•Prevalence of gastric cancer and peptic ulcers more common and severe with advancing aging

•Well established that gastric pH in the elderly can be more variable and higher then young

•50% of all people over 65 have H pylori infection and with prevalence increasing with advancing age

•30% of all people over 60 have atrophic gastritis

‘Free-living Boston Elderly’ atrophic gastritis rates– 60-60 21%– 70-79 31%– >80 37%

•High Gastric pH in the elderly• Quinine resin release study in 258 people over 65s

– 67% normal– 22% intermittent secretors– 11% had consistently pH>3.5

• pH telemetry study in 79 people over 65– 11% had pH consistently pH>5.0– Equated to ~5M Americans in 2020

•Achlorhydria in the elderly associated with poor absorption of nutrients– Ca, Fe, folic acid, Vit B6 and B12

46

Mapping the real the world of the Gastrointestinal environment

Tablet Velocity and pressure in the GI tractGastric emptying

Fluid volume within the gastrointestinal organs during fasting and after a meal by MRI.

Werner WeitschiesInstitute of PharmacyUniversity of Greifswald

47

What should a biorelevant dissolution system consider?

• Changing pH, digestive enzyme and bile levels

• Removal of dissolved drugs from the intestinal lumen

• Discontinuity of movement of the dosage forms

→ Velocities of dosage forms up to 50 cm/s

• Simulation of pressure waves of physiological power

→ Pressure values up to 300 mbar (~230 mm Hg)

• Interrupted contact of the dosage form to the medium

• Device should be able to operate with small fluid volumes

48

Dynamic Gastric Model

Fully automated, computer controlled dynamic model of human stomach

System modelled closely on the human stomach

Can process real food and drugs in real time

Includes stomach volume, peristaltic motion and continuous gastric secretions, simulating physical and biochemical processes

Has been used for some time in food research

Application to pharmaceutical products more recent.

Can be applied to a variety of the dissolution challenges.

49

TNO TIM-1 dynamic dissolution model

Stomach and small intestinal model which mimics key aspects of intestinal physiology including:• GI pH profiles and transit times

• Secretion of gastric acid and enzymes (pepsin, lipase)

• Secretion of bile, pancreatic juice

• Absorption of digested products via dialysis

Provides information on release kinetics in the intestinal lumen and availability for absorption (bioaccessibility)

Fed/fasted studies completed with micronized tablet, SDD tablet and nanomilled suspension

50

In vitro formulation comparison

Formulations tested in the TNO TIM-1 fed/fasted in vitro model of a low solubility drug at 100mg and 300mg doses

The drug has a pronounced Fed/Fasted effect in human PK studies

100mg tablet (fasted)

100mg Nano (fasted)

100mg SDD (fasted)

100mg SDD (fasted)

300mg Nano (fasted)

100mg tablet (fed)

51

In vivo formulation comparison

Formulations tested in fed/fasted dog model at a 100mg dose

52

TNO TIM-1 summary• Strong positive food effect seen in the clinic with high fat meals replicated in the TNO TIM-1 model

• Recovery results for formulations tested typically >75%

• Formulation ranking– TNO TIM-1

• SDD > nanomilled suspension > micronised tablet– In vivo dog model

• Nano Milled > SDD > micronised tablet– In addition, both demonstrated reduced variability

• Still need to prove relevance to clinical performance in humans

53

University of Greifswald – Dissolution Stress Tester

Developed specifically to mimic GI specific pressure events, GI motility and intermittent contact of dosage form with water.

Garbacz et al. Eur J Pharm Biopharm (2008) 70:421-428

Werner WeitschiesInstitute of PharmacyUniversity of Greifswald

54

The influence of different hydrodynamic mixing conditions on the dissolution of diclofenac controlled release formulations

Werner WeitschiesInstitute of PharmacyUniversity of Greifswald

Garbacz et al. Eur J Pharm Biopharm (2008) 70:421-428

55

SummaryDissolution testing has served us well over the years

Provide the quality controlled required to help ensure patients get the full benefits of the medicines we develop

Catalysed the debate leading to SUPAC, IVIVC, BCS, QbD solutions

Greater scientific understanding is going to be required moving forward

More tricky compounds and formulations coming through

Enable robust formulation development and commercialisation

Still struggling to predict clinical outcomes

pH dependant and low solubility compounds

Integrate dissolution data into predictive PK packages

Robustness of some controlled release technologies

We are now developing a much better understanding of the GI environment

Better dissolution tools in development

Going to be tough validating with new compounds and formulations

56

Many thanks toPfizer Sandwich Mark McAllister, Mei Wong, Kiyo Sugano, Kelly JonesPfizer Groton Michael Hawley, Rong Li, Kazuko Sagawa