Amorphous drugs and drug delivery systems Rades Talk... · Class II Poor solubility ... The Biopharmaceutics Classification System ... troglitazone fenofibrate M Ageing time [h]

U N I V E R S I T Y O F C O P E N H A G E N Department of Pharmacy

Dias 1

Thomas Rades

Faculty of Health and Medical Sciences

Department of Pharmacy

University of Copenhagen

Universitetsparken 2

2100 København Ø

DENMARK

Amorphous drugs and drug delivery systems


Outline

• Introduction: Solid dosage forms.

• Stability of amorphous materials.

• The preparation method for amorphous materials matters.

• Stable glass solutions can be prepared if one stays below the solubility limit of the drug in the polymer.

• Dissolution behaviour of amorphous glass solutions.

• Small molecules can also be used to make co-amorphous systems. These can be other drugs or amino acids.

• Amorphous forms of drugs may be prepared or may appear in situ.


Introduction

• The oral administration route is most desirable administration

route

– Most convenient

– Safest

– Least expensive


50% Oral 50% Other

Approx. 50% of all drugs are given orally

Marketed Drugs

4/19/03

Preformulation

21.10.20025

Characterisation of drug

absorption: Biopharmaceutical

Classification System (BCS)

Class IV

Poor solubility

Poor permeability

Class II

Poor solubility

Good permeability

Class I

Good solubility

Good permeability

Class III

Good solubility

Poor permeability

Solubility

Per

mea

bil

ity

• A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.

• A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90%

Biopharmaceutics Classification System

http://www.pharmtech.helsinki.fi


The Biopharmaceutics Classification System

Marketed drugsDrugs in Development


Market

• Total US spending on pharmaceuticals in 2012: USD 325 Billion

• Market share of poorly soluble actives in 2002: USD 110 billion

• Market is expected to increase

– More poorly soluble drugs are introduced to the market

– Increasing market in developing countries


Tekst starter uden

Sted og

Enhedens

HYDROPHOBIC LIPOPHILIC

BCS II, IV

”brickdust” ”greaseballs”

Physico-chemical properties determine formulation approach

Poorly water-soluble drugs


http://www.thinktankcomics.com/ProdImages/brick.jpg

http://www.thinktankcomics.com/ProdImages/brick.jpg

Strategies to improve solubility

Molecular level

Particulate level

Colloidal level

Prodrugs

Salt formation

Co-solvents

Cyclodextrins

SMEDDS

SEDDS

Micro-emulsions

Emulsions

Lipid solutions

Particle size

reduction

Amorphous systems

Metastablepolymorphs


Fast Track – Drug Delivery and Targeting, Y. Perrie, T. Rades, 2012, 2nd Edition


http://www.google.dk/url?sa=i&source=imgres&cd=&cad=rja&uact=8&ved=0CAkQjRwwAGoVChMIiu7m79_mxwIVAQwsCh2kMAnJ&url=http://www.pharmpress.com/Information-Help/Booksellers/Marketing-Materials/Cover-images/page3&psig=AFQjCNHitdle9XJm4MSfGgxqCxdimChcRA&ust=1441778038366435



Molecular level

Particulate level

Colloidal level

Prodrugs

Salt formation

Co-solvents

Cyclodextrins

SMEDDS

SEDDS

Micro-emulsions

Emulsions

Lipid solutions

Particle size

reduction

Amorphous systems

Metastablepolymorphs


Fast Track – Drug Delivery and Targeting, Y. Perrie, T. Rades, 2012, 2nd Edition




Crystalline compounds

Solids with orientational and

positional long-range order in

three dimensions.

Liquid crystalline compounds

State of matter in which the molecules

have long range orientational or positional

order in some but not all dimensions.

Melt / Amorphous compounds

Solids with no orientational or

positional long-range order.


Crystalline to amorphous transformation


Crystalline Drug

Solid with orientational and

positional long-range order

in three dimensions.

• low solubility

• stable

Amorphous Drug

Solid with no orientational

or positional long-range

order.

• high solubility

• instable

Amorphous form

melt

TmTgTk

super-cooled melt

Temperature

amorphous solid

crystalline solid


When do solid-state transformationsoccur?

Milling BlendingTablet coating

TablettingDryingGranulationAdministr-ation

StorageCrystallisation

Heat Pressure/

induced heat

Solvent

Shear-stress/

induced heat

Heat

Humidity

Heat

Solvent

Heat

Solvent

Shear-stress/ induced heat

Solvent

Heat

Agitation


Marketed ProductAmorphous APIs

Accolate® (zafirlukast)

Ceftin® (cefuroxime axetil)

Accupril® (quinapril hydrochlorid)

Viracept® (nelfinavir mesylate)

Amorphous solid dispersions

Cesamet ® (nabilone – PVP)

Gris-PEG® (griseofulvin – PEG)

Kaletra® (lopinavir/ritonavir –PVP/vinyl accetat copolymer )

Sporanox® (itraconazole –hypromellose)

Intelence® (etravirine –hypromellose)


Takehome messages




• Dissolution behaviour of amorhpus glass solutions.




Stability of amorphous substances






Figure1

Tf

Ta

Tm

Tg

Enth

alp

y/v

olu

me

Temperature

TK

a b

c

Liquid

Supercooled

liquid

Real glass

Equilibrium glass

Crystal

Amorphous forms - relaxation


290 300 310 320

0.2

0.3

0.4

0.5

t = 16 h

t = 12 h

t = 8 h

t = 5 h

t = 2 h

To

tal h

ea

t flo

w [W

/g]

Temperature [K]

fresh

Relaxation endotherms and temperature evolution of the glass transition temperature for QC simvastatin.


Correlation of stability with the KWW relaxation time

The extent of relaxation as a function of ageing time was calculated and is plotted. The evolution of Hrelax with ageing time for all drugs was plotted and ϕ was calculated.


step equation

Age sample for

different lengths of

time

Measure Hrelax (t, T)

and cp for different

times

Calculate H∞(0,t) 𝑯∞(𝟎, 𝒕) = ∆𝑪𝒑 𝑻𝒈 − 𝑻

Calculate φ (extent

of relaxation) for

different annealing

times

𝜑 𝑡, 𝑇 = 1 −𝐻𝑟𝑒𝑙𝑎𝑥 𝑡, 𝑇 − ∆𝐶𝑝∆𝑇𝑔(𝑡, 𝑇)

∆𝐶𝑝(𝑇𝑔 − 𝑇)

Plot the different φ

using non linear

regression to get τ

and β

𝜑 = 𝑒𝑥𝑝[ − 𝑡

𝜏 𝛽

]


0 5 10 15 20

0.0

0.2

0.4

0.6

0.8

1.0

griseofulvin indomethacin nifedipine simvastatin troglitazone fenofibrate

Exte

nt o

f re

laxa

tio

n

Ageing time [h]

0 5 10 15 20

0.4

0.6

0.8

1.0

Ageing time [h]

acetaminophen cefuroxime axetil lacidipine salsalate tolbutamide

Exte

nt o

f re

laxa

tio

n

Percentage amorphous content (█) after 30 days of storage at Tg - 20 ºCand a.) relaxation time τ(KWW) and b) stretched relaxation time τβ

(▲). Error bars for the relaxation time lie within the symbol.


Takehome messages








Amorphous indomethacin - Different

preparation methods

Diffractograms of freshly prepared amorphous form of

indomethacin prepared by different preparative techniques.



preparation methods

Thermograms of freshly prepared amorphous form of indomethacin

prepared by different preparative techniques.



preparation methods

(a) Raman spectra

(b) Scores plot

(c) Loadings plot

of all freshly

prepared

amorphous

samples.


Figure1

Tf

Ta

Tm

Tg

Enth

alp

y/v

olu

me

Temperature

TK

a b

c

Liquid

Supercooled

liquid

Real glass

Equilibrium glass

Crystal

Amorphous forms - relaxation


Stability

Effect of annealing on the KWW

relaxation function of BM γ-form

and CM γ-form.

Correlation of KWW relaxation time with

the experimentally determined stability

(onset of crystallization) for differently

prepared amorphous forms.


Effect of different cooling rates on the

stability of amorphous indomethacin

Time–temperature–

transformation

diagram, showing the

minimum cooling rate

to avoid crystallisation

(Rc).

•Tm is the melting

temperature

•Tg is the glass-

transition temperature

•Tn and tn are the

temperature and time

point at the locus,

respectively


TTT-diagram showing the

minimum cooling rate required

to obtain amorphous

indomethacin (solid line)

(a) Raman spectra of

amorphous samples of

indomethacin, prepared

from melts cooled at

various cooling rates and

(b) the corresponding PCA

scores plot


Onset time of crystallisation

for amorphous samples of

indomethacin prepared from

melts cooled at various

cooling rates and stored at Tg

– 20 °C

Influence of cooling rate of

indomethacin melts on the glass

transition temperature of the

resulting amorphous forms


Cryo-milled indomethacin

5 10 15 20 25 30 35

420 min

345 min

195 min

120 min

90 min

60 min

45 min

30 min

15 min

Inte

nsi

ty (

a.u

.)

Diffraction angle (o2)

0 min


PDF - Cryo-milled indomethacin

0 5 10 15 20

420 min

345 min

195 min

120 min

90 min

60 min

45 min

30 min

15 min

G (

r) (

a.u

.)

r (A)o

0 min

0 50 100 150 200 250 300 350 400 450

30 min

45 min

60 min

90 min

120 min

195 min

345 min

420 min

t [1

] (a

.u.)

Time (min)

0 50 100 150 200 250 300 350 400 450

50

55

60

65

70

75

80

85

90

95

100

15 min

30 min

45 min

60 min

90 min

120 min

195 min

345 min

420 min

On

set

of

cry

stal

lisa

tio

n (

oC

)

Milling time (min)0 50 100 150 200 250 300 350 400 450 500

100

150

200

250

300

350

400

450

500

30min

60min

90min

120min

420min

On

set

of

cry

stal

lisa

tio

n (

min

)

Milling time (min)


Takehome messages








Solid dispersions

Solid dispersion Number of

phases

Physical state of

phase(s)

Eutectic mixture 2 C / C

Solid solution 1 C

Complex 1 A or C

Glass solution 1 A

Amorphous

suspension

2 A / A or A / C

Glass (amorphous) solutions are ideal for increasing

dissolution

• Maximally reduced particle size (molecular)

• Amorphous drug

• Intimate presence of water-soluble excipient


• Liquid to amorphous solid – freezing-in of disorder:

• Spray drying

• Melt extrusion• Super critical fluids

• Co-precipitation

• Crystalline solid to amorphous solid – inducing

disorder:

• Ball milling

Preparation of glasses and glass solutions

Spray

drying from

solution

Crystalline Amorphous


Glass solutionMolecularly dispersed drug in an amorphous polymer carrier:

Challenges • Thermodynamic unstable

– Phase separation and crystallization

Objective• Ensuring thermodynamic stability

– The drug has to be soluble in the polymer– The drug load needs to be below the solubility

45


Determination of drug solubility in polymers

Equlibrium saturated state is achieved from

demixing of a supersaturated solution

After equlibrium at a given annealing

temperature above the Tc, a change in Tg is

correlated to a given solubility according to

the Gordon-Taylor equation

The Flory-Huggins model is then applied to

extrapolate the solubility curve to room

temperature


IMCPVP

PVP

IMC

IMC

IMC

IMC

IMC

IMC 1 ,1

vvXX

X

v

2PVPPVPIMC

11ln

11vvv

TTR

H

am

m

IMCIMCgIMCg(PVP)

IMCg(PVP)

IMCXTTXTTK

XTTKX

gg

g

IMCp

PVPp

C

CK

ΔHm and Tm are the enthalpy of fusion and melting temperature for the drug, R is the gas constant, Ta is the annealing temperature, λ is the molar volume ratio of the polymer and drug, χ is the Flory-Huggins interaction parameter and vIMC

and vPVP are the volume fractions of drug and polymer respectively

Obtain supersaturation

• Spray drying

of a solution of drug and polymer in a volatile solvent

• Film casting

of same solution on a hot teflon plate

• Ball milling

for long enough to ensure crystalline drug is amorphized

• Hot melt extrusion

• Melt granulation


Equilibrium solubility of IMC (XIMC) in PVP K12 as a function of annealing temperature (Ta). Green diamonds ball milling, red circles spray drying, and blue squares from film casting.

The data previously reported by Mahieu et al. (2013) is presented as black crosses (x).


Comparison of the three methods

49

Film casting

Spray drying

Ball milling

Residual plot



50

Film castingSpray dryingBall milling

Solvent evaporationMechanical forces

Ordered crystalline state

Solid dispersion Solid dispersion

Disordered state (solution)

Time-consuming (8 hours) Evaporation Instant (<1 second)Crystal lattice interruption



51

Film castingSpray dryingBall milling

Solvent evaporationMechanical forces

Raman microscopy

Heterogenous mixture Homogenous mixture

*Patterson et al., 2007


Summary

52

MethodPreparation

timeAPI usage

Product stability

ReproducibilityFit to Flory-

Huggins

Ball milling

8 h ≈ 1 g Weeks Good Bad

Film casting

< 1 h < 1 g Months Bad Good

Spraydrying

1 h > 1 g Months Good Good


Equilibrium solubility of IMC (XIMC) in PVP of different molecular weight as a function of annealing temperature (Ta).


Materials

54

Celecoxib (CCX)Low aqueous solubility

Polyvinylpyrrolidone (PVP)HydrophilicVery hygroscopic

Polyvinyl acetate (PVA)HydrophobicAnhygroscopic

Polyvinylpyrrolidone/vinyl acetate (PVP/VA) copolymer compositions (70/30, 60/40, 50/50 and 30/70 w/w)

Polyvinylpyrrolidone/vinyl acetate (PVP/VA)


Demonstration of the recrystallization method

55

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

25,0 45,0 65,0 85,0 105,0 125,0 145,0 165,0

Example of a solubility curve (CCX:PVP/VA 60/40)

- Extrapolation using The Flory-Huggins equation

- Prediction interval from a statistical analysis

Temperature [°C]

Pre

dic

ted

so

lub

ility

[w

/w]


Results

56

Liquid Monomer Solubility Approach

Recrystallization Method


Results

57



Results

58


Plateau


• LMSA does not take physical differences between monomer and polymers into account – Results in linearity and possible overestimation

of drug solubility

• It is possible to obtain the same solubility with less VP in the copolymer chain– Enhanced physical stability due to decreased

water absorption

59


• This study found the Liquid Monomer Solubility Approach may overestimate drug-polymer solubility since it does not take the physical differences between monomers and polymers into account

• The predicted solubilities from the Recrystallization Method indicated that the solubility reaches a plateau due to size differences between the drug and interacting monomer molecules (VP)

• Copolymers can theoretically be customized to fit any given drug with a ratio and sequence of monomers that provide the optimal drug-polymer solubility and physical stability.

60


Takehome messages








The “spring and parachute” effect

62

Brouwers et al. J. Pharm. Sci. 2009, 98 (8), 2549-2572



63


Amorphous drug witha polymer

Amorphous drug



64


Amorphous drug witha polymer

Amorphous drug


Aims

65

• What is the influence of a copolymers composition on non-sink in vitro dissolution behavior of amorphous solid dispersions

• What is the influence of a copolymers composition on in vivo performance of amorphous solid dispersions in rats

• Is a simple non-sink in vitro dissolution method predictive of in vivo performance (in vitro – in vivo correlation)


Materials

66

Vinylpyrrolidone (VP) Vinyl acetate (VA) Celecoxib (CCX)

Hydrophilic Hydrophobic Poorly water-soluble ~ 3 μg/ml

High Tg Low Tg Weak acid pKa = 11.1

• PVP/VA is a synthetic copolymer produced by random free-radical polymerization of VP and VA in different monomer ratios (30, 50, 60 and 70% VP)


Non-sink in vitro dissolution

67

CCX-PVP/VA 50/50

CCX-PVP/VA 60/40CCX-PVP/VA 70/30

CCX-PVP

CCX-PVP/VA 30/70

CCX amorphous

CCX crystallineCCX-PVA



68

CCX-PVP/VA 50/50


CCX-PVP

CCX-PVP/VA 30/70

CCX amorphous




69

CCX-PVP/VA 50/50


CCX-PVP

CCX-PVP/VA 30/70

CCX amorphous



In vivo performance in rats

70

CCX-PVP/VA 60/40CCX-PVP


CCX amorphous

CCX-PVP/VA 30/70CCX crystalline

CCX-PVA



71



CCX amorphous


CCX-PVA



72



CCX amorphous


CCX-PVA


• Expected of in vivo performance based on AUC0-4h from non-sink in vitro dissolution:

– Amorphous CCX perform better than crystalline CCX

– CCX-PVP/VA 30/70 perform better than crystalline CCX

– Crystalline CCX perform equal or better than CCX-PVA

– Amorphous CCX perform equal to CCX-PVP/VA 30/70

– CCX-PVP/VA 50/50, 60/40, 70/30 and CCX-PVP perform

better than any of the other four formulations

– CCX-PVP/VA 50/50 perform better than CCX-PVP

In vivo – In vitro correlation

73


Conclusions

74

• Increasing the hydrophilic VP content increased the dissolution rate of the amorphous solid dispersion (“spring effect”)

• Increasing the hydrophobic VA content increased the crystallization inhibition of the amorphous solid dispersion (“parachute effect”)

• Both in vitro and in vivo it seems that there was an optimal ratio between the dissolution rate enhancing (VP) and crystallization inhibiting (VA) monomers in the copolymer (around 50-60% VP)

• A correlation between in vitro AUC0-4h and in vivo AUC0-24hindicated that the non-sink in vitro dissolution method was predictive


Takehome messages








Drug Drug Combinations

Naproxen

• BCS class II

• Non-steroidal anti-inflammatory drug (NSAID)

• Side effect: Gastro-intestinal disorders

Cimetidine

• H2-receptor antagonist

• BCS class III

• Used in the treatment of gastro-intestinal disorders

• similar dosing range for NAP&CIM


Individual APIs before and after milling - XRPD

Tg = 36.1 2.0 °C

Tg of quench-cooled NAP = 6.2 0.6 °C


Co-milled APIs at different ratios XRPD & DSC

• All ratios result in X-ray amorphous mixtures

• No trace of crystallinity in DSC

Tg= 40.2 1.1 °C Tg= 34.5 0.3 °C Tg= 31.5 0.7 °C

DSC

X

RP

DU N I V E R S I T Y O F C O P E N H A G E N Department of Pharmacy

Physical stability - XRPD

60-day storage at dry conditions

Not the highest Tg

after preparation

Still stable after 6 months

Most stable


Intrinsic dissolution

• Compared to crystalline APIs co-amorphous NAP-CIM shows – 4-fold increase in IDR of NAP

– 2-fold increase in IDR of CIM

• Amorphous CIM alone shows no increase in IDR compared to crystalline CIM– likely due to immediate crystallization

upon dissolution

• Co-amorphous NAP-CIM – stays amorphous upon dissolution

– offers synchronized release of the two drugs

Not significantly different (95% conf. level)


Indomethacin - Naproxen


• both BCS class II

• Preparation method: Quench cooling

Cl

N

O

OH

CH3

O

OCH3

CH3 OH

O


DSC – homogeneous mixtures




Experimental vs. Gordon Taylor

Excess component




DSC and

Gordon-Taylor

equation





XRPD: Stability Day 21

NAP

NAP

IND


Physical Stability of quench cooled IND-NAP

Influence of NAP-IND ratio


Beyer et al. 2015, (unpublished data).

5

15

25

35

45

55

0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1

Tem

par

atu

re

Weight fraction NAP

5

15

25

35

45

55

0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1

Tem

par

atu

re

Weight fraction NAP

Physical Stability of ball milled NAP-CIM

Influence of NAP-CIM ratio


NAP:CIM1:1

NAP:CIM2:1

NAP:CIM3:1

NAP:CIM1:2

49.2 °C 51.5 °C 50.7 °C 48.2 °CTg

Most stable

Similar Tgs

Drug – Amino acids

• Aminoacids may interact on a molecular level with drugs

• From literature we know: HIS and ARG are able to form an amorphous phase upon freeze drying

• Interactions between aminoacids and drug molecules at their biological target site

Use of receptor aminoacids as potential interactors?


BCS class II drug candidates with active

site and aminoacids from active site

• Carbamazepine (Na-chanal; PHE, TRP)

• Indomethacin (COX2; ARG, TYR)

• Naproxen (COX2; ARG, TYR)



Prepration of co-amorphous blends


Sample content Tg (°C) Sample content Tg (°C)

IND 36.7 ± 0.8 CBZqc* 56.1 ± 0.2

IND-ARG 64.1 ± 1.4 CBZ-TRP 81.0 ± 0.6IND-PHE 47.8 ± 2.9 CBZ-PHE-TRP 75.1 ± 1.1

IND-TRP 68.7 ± 2.6 CBZ-ARG-TRP 65.4 ± 1.1

IND-PHE-TRP 63.1 ± 0.8

IND-ARG-PHE 77.9 ± 3.4

Glass transition temperatures


Physical stability study – 40°C over 1 year

CBZ, 7days

CBZ-TRPCBZ-PHE-TRPCBZ-ARG-TRPIND-ARG-PHE

IND-PHE-TRPIND-TRPIND-ARG

IND-PHE, 6month

IND, 7 days


Single component amorphization

5 10 15 20 25 30 35

3 hours

Absorb

ance

Angle/2 ()

Indomethacin

0 min

5 min

15 min

30 min

45 min

60 min

90 min

5 10 15 20 25 30 35

Absorb

ance

Angle/2 ()

Furosemide

0 min

5 min

15 min

30 min

45 min

60 min

90 min

3 hours

5 10 15 20 25 30 35

Absorb

ance

Angle/2 ()

Tryptophan

0 min

5 min

15 min

30 min

45 min

60 min

90 min

3 hours


Reference: Jensen et al. 2015 (unpublished data).

Co-amorphization

5 10 15 20 25 30 35

crystalline tryptophan

crystalline indomethacin

60 min

45 min

30 min

15 min

0 min

90 min

Indomethacin-tryptophan

Absorb

ance

Angle/2 ()

5 min

5 10 15 20 25 30 35

crystalline tryptophan

crystalline furosemide

Furosemide-tryptophan

Absorb

ance

Angle/2 ()

0 min

5 min

15 min

45 min

30 min

60 min

90 min


DSC – Glass transition temperature (Tg)

0 2 0 4 0 6 0 8 0 1 0 0

0

2 5

5 0

7 5

1 0 0

1 2 5

1 5 0

g la s s t r a n s it io n t e m p e r a t u r e

M ill in g t im e (m in )

Tg

(C

)

in d o m e th a c in - t ry p to p a h n

fu ro s e m id e - t ry p to p a h n

fu ro s e m id e

in d o m e th a c in

tr y p to p h a n

Sample content Actual Tg (°C) Theoretical Tg (°C)

Amorphous furosemide 78.6 ± 0.53 -

Amorphous indomethacin 45.0 ± 0.98 -

Amorphous tryptophan 139.0 ± 0.68 -

Co-amorphous furosemide-Tryptophan 110.8 ± 0.56 102.4

Co-amorphous indomethacin-Tryptophan 91.0 ± 0.80 74.0


Supersaturation


Comparison to glass solutions?


Summary Drug - AAs

• Highly stable co-amorphous mixtures• Improved dissolution• Interactions possible• Comparable with PVP solid dispersions• Weight ratio between 1:0.5 and 1:1.5


Takehome messages








In situ amorphisation

Molecular structures of indomethacin and Eudragit® E

X-ray diffractograms of compacts of γ-IMC Eudragit® E physical

mixtures at 3:1, 1:1 and 1:3 drug-to-polymer ratios, and the

corresponding compacts after immersion at pH 6.8.

In situ Quench cooled

IMC - 44.5 ± 0.1 °C

IMC - Eudragit® E 3:1 58.1 ± 1.0 °C 61.9 ± 0.3 °C

IMC - Eudragit® E 1:1 54.4 ± 0.2 °C 57.4 ± 1.8 °C

IMC - Eudragit® E 1:3 50.1 ± 0.9 °C 49.1 ± 0.2 °C

Eudragit® E 56.9 ± 0.5 °C

Glass transition temperatures of samples after immersion at pH 6.8 and

IMC Eudragit® E glass prepared by quench cooling

Takehome messages









Dias 107

Thank you for your attention!


Documents

Amorphous drugs and drug delivery systems Rades Talk... · Class II Poor solubility ... The Biopharmaceutics Classification System ... troglitazone fenofibrate M Ageing time [h]