Role of Supersaturation in Enhancing

Biological Exposure in Preclinical Models

Ping Gao, Ph.D.

Global Pharmaceutical Life Cycle Technology

Abbott Laboratories

2008-5 AAPS 1
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 2
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 3
 Approaches for Poorly Soluble Drugs

p Salt Form / pH modulation

p Particle size reduction
p Amorphous drug/ solid dispersion
p Solubilization
‰ Cosolvent based
‰ Surfactant based (with and without lipid)
p Complexation (i.e., cyclodextrins)
p Prodrug

2008-5 AAPS 4
 Drug Transport and Absorption

Supersaturation phenomena commonly occur during

drug transport and absorption in GI tract

2008-5 AAPS 5
Supersaturation from Pharmaceutical Salts

Salt of acidic (or basic) drug

p Usually shows rapid dissolution in gastric fluid
p Drug solution upon initial dissolution of a salt can be
highly supersaturated with respect to the free acid (or
base) form
‰ Acidic drug: precipitates in stomach (low pH 1-3)
‰ Basic drug: precipitates in small intestines (pH 5-8)
p May or may NOT improve exposure as compared to the
crystalline free form and this is most likely determined by
the precipitation kinetics

2008-5 AAPS 6
 Dissolution of Salt and Precipitation
∆ P123
p Celecoxib Na salt
‰ Cox-2 inhibitor
‰ MW = 381.4 • F127
‰ Aq. solubility ~ 5 µg/ml
‰ pKa=11.1 (very weak acid) VE-TPGS
‰ Log P ~ 4
‰ Dissolution limited absorption
from marketed capsule

Dissolution of crystalline celecoxib Na salt (PG

solvate trihydrate) from solid formulations at 37°C in
SGF (pH 1.7). Excipients used were Pluronic P123,
Pluronic F127, and VE-TPGS.

Guzman et al. JPS, 96, 2686 (2007)

2008-5 AAPS 7
 Supersaturation from Cosolvent
Cosolvent of poorly water soluble drugs:
p No solubilization capacity upon mixing with water
p Rapid mixing with water yields a highly supersaturated state
p Precipitation yields large particles and aggregates
p Difficult to achieve significantly improved exposure as compared to
other formulation approaches
Drug Concentration

Drug solubility in cosolvent and

water mixture

Drug concentration- dilution profile

Ct
Degree of supersaturation = [Ct-Cs]/CS
Cs

Cosolvent Dilution Factor Water

2008-5 AAPS 8
 Supersaturation from Prodrug
p Prodrug intended to improve solubility (common approach)
‰ Attach an ionizable moiety onto the parent drug and make
appropriate salt
‰ Rapidly dissolve and convert back to parent drug in vivo (by
enzymatic or chemical cleavage)
‰ Yield a temporally supersaturated state of the parent drug and this
could result in precipitation of the parent drug

Drug Promoiety + Drug

Derivatization Transformation
in vivo

New chemical entity

Promoiety Drug Promoiety Drug

2008-5 AAPS 9
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 10
Supersaturation and Drug Absorption

p Theoretical consideration

Intestinal Absorption: J 3 Hr. = Pe * Cs * 2πD* L * 3Hr

With Dose = 250 mg (Max Pe): Small Intestine ~ 350 cm

3.5 cm
Cs = 1 μg/ml, J 3 Hr = 3-5% Abs . Residence Time ~ 3 hr.

Cs = 10 μg/ml, J 3 Hr = 30-50% Abs .

Cs = 20 μg/ml, J 3 Hr = 60-100% Abs . Precipitation
inhibitor
Cs =40 μg/ml, J 3 Hr = >100 % Abs .
Nucleus

p Concept: Can we design a formulation that achieves

and sustains a temporally supersaturated solution
(high free drug conc.) in vivo ?

2008-5 AAPS 11
 Supersaturation and Crystallization

Manipulate the
supersaturated state and
the CNC ………..with
polymeric crystallization
inhibitor (PCI)

Cs

2008-5 AAPS 12
 Supersaturation and Crystallization

p The degree of supersaturation (Δ/Cs) is a critical factor in

formulation design
‰ Driving force in precipitation
‰ Δ/Cs too high Æ rapid precipitation
‰ Desire to sustain the supersaturated state for 2-4 hours (small
intestine transit time).

p Polymeric substances have been demonstrated

to retard the drug precipitation process

p Incorporate a polymeric crystallization inhibitor in the

formulation to stabilize the supersaturated state

2008-5 AAPS 13
 Polymeric Crystallization Inhibitors

Commonly used PCI:

OR C H 2 OR
O
OR
OR
O O
CH2OR OR
n

R = H, CH3 , CH2 CH OH CH3

HPMC HPMCAS
(with different MW (different substitution)
different substitution)

PVP (different MW)

2008-5 AAPS 14
 Selected References
p Higuchi, Physical chemical analysis of percutaneous absorption process. J.Soc.Cosmet. Chem.
11: 85-97 (1960).
p Simonelli, Mehta, Higuchi. Inhibition of Sulfathiazole Crystal Growth by Polyvinyl Pyrrolidone.,
J.Pharm.Sci., 59, 633-638 (1970).
p Davis, Hadgraft. Effect of supersaturation on membrane transport: 1. Hydrocortisone acetate.
Int. J. Pharm. (1991), 76(1-2), 1-8.
p Loftsson, Fridriksdottir, Gudmundsdottir. The effect of water-soluble polymers on aqueous
solubility of drugs. Int. J. Pharm. 127 (1996) 293.
p Hadgraft, Raghavan, Trividic, Davis. Effect of cellulose polymers on supersaturation and in vitro
membrane transport of hydrocortisone acetate. Int. J. Pharm. 193 (1997) 231.
p Raghavana, Trividica, Davisb, Hadgraft. Effect of cellulose polymers on supersaturation and in
vitro membrane transport of hydrocortisone acetate. Int. J.Pharm.193 (2), 231-237 (2000).
p Hadgraft, Raghavan, Kiepfer, Davis, Kazarian. Membrane transport of hydrocortisone acetate
from supersaturated solutions: the role of polymers. Int. J. Pharm. 221 (2001) 95.
p Hadgraft, Iervolino, Cappello, Raghavan. Penetration enhancement of ibuprofen from
supersaturated solutions through human skin. Int. J. Pharm. 212 (2001) 131.
p Hadgraft, Raghavan, Trividic, Davis. Crystallization of hydrocortisone acetate: influence of
polymers. Int. J. Pharm. 212 (2001) 213.
p Moser, Kriwet, Kalia, Guy. Stabilization of supersaturated solutions of a lipophilic drug for
dermal delivery. Int. J. Pharm. 224 (2001) 169.
p Gao, Morozowich. Development of Supersaturatable SEDDS (S-SEDDS) Formulations for
Improving the Oral Absorption of Poorly Soluble Drugs. Expert Opinion in Drug Delivery 3(1), 97-
110 (2006).

2008-5 AAPS 15
 Design of Supersaturatable Formulations

Supersaturated State
generated upon administration

Element 1:
Rapid dissolution to generate a How to assess? Impact in vivo
supersaturated state upon dosing exposure?
in vivo
Element 2: Sustains the
supersaturated state with the
polymeric crystallization inhibitor

Achievable?

2008-5 AAPS 16
 Liquid (S-SEDDS) Approach
p Drug dissolved in a SEDDS vehicle (solvent, surfactant, lipid) with
polymeric crystallization inhibitor (PCI)
p Vehicle emulsifies upon mixing with water
p PCI stabilizes a supersaturated state of the drug

Emulsification with
gentle agitation
CH3
OH
H3C CH3
OH

Drug
O O H3C
NH
CH3 O O
OH SO2
NH
H3C N
F3C SO2
O O N
F3C

Solvent
NH
SO2

N CH3
F3C OH
CH3 H3C
OH
H3C O O

Lipid
NH
CH3 O O
OH SO2
NH
H3C N
SO2 F3C
O O N
F3C
NH
SO2

Surfactant
N
F3C
CH3
OH
CH3 CH3 H3C
OH OH
H3C H3C O O
NH

Polymer
O O O O
SO2
NH NH

Softgel F3C
N
SO2

F3C
N
SO2 F3C
N

Softgel Water Microemulsion

2008-5 AAPS 17
 Solid Formulation Approach

p A poorly soluble drug could achieve a supersaturated

state via
‰ Salt form (rapid dissolution)
‰ Amorphous form
‰ Formulation approach with enhanced dissolution

p Process consideration for solid dispersions that may

achieve a supersaturated state
‰ Spray drying
‰ Melt extrusion
‰ Other methods for preparing solid dispersions

p Use of polymer to stabilize a supersaturated state

2008-5 AAPS 18
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 19
 In Vitro Evaluation

p To screen and optimize the performance of super-

saturatable dosage form
p To assess the extent of supersaturation in a biorelevant
environment
‰ Determine the free drug concentration in a supersaturated state
‰ Determine the duration of the supersaturated state
‰ Determine drug precipitation kinetics and its particle size
distribution
‰ Determine crystallinity of the precipitates
‰ Establish the relevance of the in vitro supersaturated state vs.
the in vivo exposure

2008-5 AAPS 20
 In Vitro Evaluation Methods

p Biorelevant release test

p Artificial stomach-duodenum model

‰Hawley et al. JPS. 95(1) 116-125, 2006

p Biphasic dissolution test

p FBRM characterization of precipitation

2008-5 AAPS 21
 Measuring Supersaturation

p Challenges in determining free drug concentration

‰ Supersaturated state is a dynamic, meta-stable system
‰ Drug concentration can change as a function of time
‰ Solid drug particles exist along with supersaturated solution

p Analytical techniques for free drug determination

‰ Centrifugation
‰ Ultracentrifugation
‰ In situ solution NMR (high sensitivity)
‰ Dialysis
‰ Micro-dialysis
‰ Water-octanol partition (Î Biphasic release test)

2008-5 AAPS 22
 Biorelevant Release Test
p Biorelevance
‰ Dissolution media
• simulated gastric fluid (SGF): 0.01 M HCl + 0.15M NaCl, pH 2
• simulated intestinal fluid (SIF): 0.05M phosphate buffer, pH 6.5
‰ Total volume: 50 to 200 mL
• physiological consideration
• mimic oral dosing regime in dog and human
‰ Non-sink condition to assess supersaturation
‰ Stirring rate: 50 - 100 RPM, 37 °C

p Drug concentration determination

‰ Filtrated with 0.8 μm filter (remove large particle size)
‰ Total drug concentration = [Drug]solubilized+[Drug]free+[Drug]small particle
‰ Sampling from 0.25 to 4 hours

2008-5 AAPS 23
 Biphasic Dissolution Test
‰ Drug dissolves in an aqueous phase and partitions into an organic phase
‰ Accumulation of drug in the organic phase mimics drug partitioning
through GI membrane
‰ Suitable for a variety of dosage forms

Media Filter USP 2 with

Dual Paddle
Fiber optic UV

Organic layer
Flowcell

Aqueous layer

Returned Media

2008-5 AAPS 24
 Biphasic Dissolution System

Flowcell

Pump USP-2 System

2008-5 AAPS 25
 FBRM Characterization of Precipitation
To monitor precipitation kinetics and the particle size
FBRM probe
distribution by the use of FBRM probe (Model S400E)

Focused Beam Reflectance Measurement

100 ml
Water, RT

Peddle at
100 RPM

0.45 g SEDDS formulation

2008-5 AAPS 26
 Why FBRM?

p Real time in situ measurement of both the dimension

and number of solid precipitate particles in test media to
assess precipitation kinetics as a function of time
p Provide insight in the dominate process mechanisms
(e.g. nucleation, growth, agglomeration)
p A tool for characterizing and optimizing the
performance of supersaturatable formulations with key
variables

2008-5 AAPS 27
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 28
 Case Review: Paclitaxel
O

p Paclitaxel O
O
O O
OH
‰ MW = 853 NH O
OH

‰ Aqueous solubility < 0.3 μg/ml HO

O
H
O
O

‰ No ionizable groups O O

‰ Low solubility in commonly pharmaceutically acceptable

solvents/lipids
p PK Evaluation
‰ Marketed IV product (BMS TAXOL® with 50% Cremophor EL)
‰ Extremely low oral F%
‰ P-gp substrate
‰ No commercial product for oral administration

2008-5 AAPS 29
 Paclitaxel Formulations

Ingredients “S-SEDDS” “SEDDS” “Taxol”

Paclitaxel 57 mg 62.5 mg 6.8 mg

PEG 400 151.5 mg 156.25 mg --

Absolute EtOH 151.5 mg 156.25 mg 423.2 mg

Cyclosporin -- -- --

Cremophor EL 400 mg 417 mg 570 mg

Glyceryl dioleate 190 mg 208 mg --

HPMC-E5 50 mg -- --

Total 1000 mg/g 1000 mg/g 1000 mg

Surfactant : Drug 7:1 6.7 : 1 84 : 1

Gao et al, J.Pharm.Sci. 92 (12), 2395-2407 (2003).

2008-5 AAPS 30
 Case Review: Paclitaxel
Biorelevant Release Test (50X-dilution)
Paclitaxel Conc in (mcg/ml) 1000

800 Curve 1 /2 (duplicate) S-SEDDS with 5% HPMC

600

400

200
Curve 3 /4 (duplicate) SEDDS without HPMC
0

0 20 40 60 80 100 120
Time (Min.)
Gao et al, J.Pharm.Sci. 92 (12), 2395-2407 (2003).

2008-5 AAPS 31
 Case Review: Paclitaxel
400

RatInOral
Vivo Bioavailability
Rat Study (n=8) (n=8)
S-SEDDS
300
Paclitaxel conc. (ng/ml)

5% HPMC.….makes the difference!

200 12X -Cmax and 10X-AUC due to

supersaturated state

100

Taxol
SEDDS

0 1 2 3 4 5 6 7 8
Time (Hr)

Gao et al, J.Pharm.Sci. 92 (12), 2395-2407 (2003).

2008-5 AAPS 32
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 33
 Case Review: Drug X

p Physicochemical Property
‰ MW ~ 400
‰ M.P. ~ 170 °C
‰ Aq. solubility ~ 3 µg/ml (not ionized in the physiological pH condition)
‰ Dose = 200 mg
‰ Log P = 3.5
p PK/PD Evaluation
‰ Incomplete absorption with conventional solid dosage forms
‰ Desire rapid onset and high Cmax for pain relief
p Design of High Load (200mg/unit) Formulation
‰ Liquid S-SEDDS
‰ Solid dispersion with amorphous drug

2008-5 AAPS 34
 HPMC: A Critical Component

In Vitro (50X dilution) In Vivo (Dog)

6000 200 mg dose
D r u g X C o n c . ( m g /m L )

Average of 6 dogs
4 5000

D r u g X C o n c . (n g /m l)
SEDDS with 4% HPMC
3 4000
SEDDS with 4% HPMC (HGC)

3000
2
SEDDS without HPMC 2000
1 SEDDS w/o HPMC (HGC)
1000
0
0
0 1 2 3 4 5 6
0 5 10 15
Time (hr) Time (Hrs)

‰ 4% HPMC in S-SEDDS results in 3X enhancement of AUC and Cmax!

Gao et al, Expert Opinion in Drug Delivery, 3(1), 97-110 (2006)

2008-5 AAPS 35
 HPMC: A Critical Component
In Vitro (100X dilution) In Vivo (Dog)
1.5 8000 6 dogs (Crossover)
D ru g X C o n c . ( m g /m l)

D r u g X C o n c ( n g /m l)
7000
SEDDS in HPMC cap
6000
1 SEDDS + 4.7% HPMC in HGC
5000
4000

0.5 3000
2000
1000
0 SEDDS without HPMC in HGC
0
0 1 2 3 4
Time (hr) 0 5 Time (hr) 10 15

‰ A HPMC capsule shows the same effect as ~4% HPMC powder

Gao et al, Expert Opinion in Drug Delivery, 3(1), 97-110 (2006)

2008-5 AAPS 36
 PK of Drug X S-SEDDS in Human
More rapid and complete absorption with S-SEDDS softgel
- 3.5 X Cmax with Tmax ~ 1 hr,
- 2X AUC
2000
Softgel

Suspension
1500
Drug X Conc. (ng/ml)

Commercial

N=12 (Cross-over)
1000

“Golden Standard”
500

0
0 2 4 6 8 10 12
Time (Hr)
Gao et al, Expert Opinion in Drug Delivery, 3(1), 97-110 (2006)

2008-5 AAPS 37
 Product Presentation

p Softgel: stability and manufacturability proven

p HPMC capsule: A new promising dosage form

Softgel with SEDDS in

HPMC suspended HPMC capsule
2008-5 AAPS 38
PK of Amorphous Drug X in Solid Dispersions
Rapid and complete absorption
6000
Dog (n=6, cross-over)
Spray drying dispersion in capsule
5000

4000
Dru g X Co n c (n g /mL )

HME (HPMCAS-LG) in capsule

3000
HME (HPMC/PVP) in capsule

2000

1000
Market Capsule

0
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00
Time (hr)

2008-5 AAPS 39
 Case X: Precipitate Solids
p Precipitates of Drug X from HPMC containing solution
‰ Amorphous nanoparticles/aggregates
‰ ~ 1-10% HPMC found in drug aggregates

500 XRD ofcelecoxib susp w/HPMC

the drug ppt
in HPMC soln
400

ZH-2
quartz blank
In te n s ity ( c o u n ts )

300

200
Sample
100

20μm
0
M:\MHFiles\Projects\Celecoxib\formulations\992R222A ZH suspensions HPMC.opj Quartz blank 20μm
5 10 15 20 25 30 35
Two Theta (degrees)
Two Theta (degrees) 01/31/2002

Pictures from polarized microscope

2008-5 AAPS 40
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 41
 Case Review: AMG 517

p Physicochemical properties
‰ MW =430
‰ pKa =1.8
‰ Aq. solubility ~ 0.05 μg/ml (within the pH range of 2-10)
‰ cLog P = 5.1
‰ M.P. = 232 °C
p Preliminary PK Evaluation
‰ Targeted dose: 12.5 mg (human)
‰ Low and highly variable oral exposure with conventional solid
dosage forms
p New Formulation approaches
‰ S-SEDDS
‰ Spray drying dispersion

2008-5 AAPS 42
 AMG 517: Precipitation Kinetics (con’t)
Effects of 30% Tween80 Varying RPM
Precipitation kinetics is slightly
5000

4500
affected by different agitation speed
50 RPM (n=2)
4000
100 RPM (n=2) (50-200 rpm).
Counts/ Sec (1-10 um)

3500
200 RPM (n=2)
3000

2500
This suggests a spontaneous
2000
nucleation due to a high degree of
1500

1000 supersaturation!
500

0
Particle Size Distribution of 30% Tween 80 at Varying Speeds
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510
Records (6 rec=1 min)
250

200 50 RPM

100 RPM
Counts/ Sec 150
200 RPM

100

50

0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
P.Gao et al. JPS in press Particle Size (µm)

2008-5 AAPS 43
 AMG 517: Precipitation Kinetics
HPMC Effect: The mean PSD at t=60 min Tween Effect: The mean PSD at t=60 min
-- Formula contains 30% Tween80 --Formula contains 10 - 40% Tween 80
-- without and with 5% HPMC-E5 -- without HPMC
250 800

Without HPMC 10% Tween80 (n=2)

200
600

150
Counts/Sec

Counts/Sec
400

100 20%Tween80 (n=2)

30%Tween80 (n=2)
200
50

40%Tween80 (n=2)
With HPMC-E5
0
0
0 25 50 75 0 25 50 75
Particle Size (µm ) Particle Size (µm )

2008-5 AAPS 44
 AMG 517: PCI Effect (PSD profile)
PCI effects upon precipitation kinetics (S-SEDDS with 30%Tween80)
-- different type of polymer at 5% in the prototype formulations
Particle Size Distribution of 30% Tween w/ 5% Polymers
800

700

600 E5
AS
500
Counts/ Sec

E50
400 E4M
300 K3
K100LV
200
PVP 12PF
100 PVP K30
0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Particle Size (µm)

2008-5 AAPS 45
 AMG 517: PCI Effect (in vitro release)
0.14
w ithout E5LV
0.12
0.5%E5LV

g/ml)
Conc. effect of HPMC-E5LV 0.10 2%E5LV

DrugYConc. (m
-- S-SEDDS with 30% Tween80 0.08
5%E5LV
10%E5LV
0.06

0.04

0.02

0.00
0 50 100
Tim e (m in.)

0.14
E5LV
0.12 E50LV
g/ml)

E4M
0.10
MW effect of HPMC (fixed 5%)
onc. (m

K3LV
0.08
-- S-SEDDS with 30% Tween80 K100LV
rugYC

0.06

0.04
D

0.02

0.00
0 50 100
Tim e (m in.)

2008-5 AAPS 46
 AMG 517: Precipitated Solids
Precipitated solids from Precipitated solids from
SEDDS with 20%Tween80 SEDDS with 30%Tween80
Intensity (counts)

Intensity (counts)
15000

2500

2000

10000
1500
Without HPMC

1000

5000
500 Without HPMC

0
5 10 15 20 25 30 35 40
2Theta (°)
0
5 10 15 20 25 30 35 40
2Theta (°)
Intensity (counts)

Intensity (counts)
1500 1200

1000

1000
800

600

500
400
With 5%HPMC-E5 With 5%HPMC-E5
200

0
5 10 15 20 25 30 35 40 0
2Theta (°)
5 10 15 20 25 30 35 40
2Theta (°)

2008-5 AAPS 47
 PK of AMG 517 Formulations

1600 Mean PK profile in m onkeys (n=6, cross-over)

Dose of AMG 517 = 12.5 m g
1400
AMG 517 Plasma Conc.

1200 FIH Aq. suspension

S-SEDDS
1000
Spray drying dispersion
(ng/ml)

800

600

400

200

0
0 10 20 30 40 50
Tim e (Hr)
P.Gao et al. JPS in press

2008-5 AAPS 48
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 49
Roles of Polymeric Crystallization Inhibitor
PCI Inhibits Nucleation

x Crystalline
Nuclei
Crystalline phase

With PCI

Amorphous Amorphous
Homogeneous aggregates
solution
Critical Nuclei Intermediate/final stage

PCI’s roles (such as HPMC) are proposed:

‰ Adsorbs on the nuclei surface and prohibits formation of crystalline nuclei/ lattice
‰ Incorporated into aggregates and the precipitated solids are drug/polymer composites

2008-5 AAPS 50
 Outline

p Supersaturation and Drug Absorption

p Design of Supersaturatable Formulations
p In Vitro Assessment of Supersaturation and
Precipitation Kinetics
p Case Studies
‰ Paclitaxel
‰ Drug X
‰ AMG 517
p Crystallization Inhibition by Polymers
p Conclusions

2008-5 AAPS 51
 Conclusions
p Supersaturatable formulations are an effective delivery
approach to overcome the oral absorption challenge of
poorly water soluble drugs
p Major considerations in designing supersaturatable
formulations
‰ The degree of supersaturation upon dissolution is critical
‰ The appropriate type and level of a polymeric crystallization
inhibitor is critical
‰ Dosage form and manufacturing process
p Amorphous drug precipitates may partially contribute to the
supersaturated state and improved exposure
p Appropriate in vitro characterizations should be
established
p Drug-polymer interaction is not fully understood--a
challenging area for further research.
2008-5 AAPS 52
 Acknowledgements

Pfizer/Legacy Pharmacia Amgen Abbott

Walter Morozowich Paco Alvarez John Skoug
Mike Hageman Chandra Ma
Phil Nixon Lan Li
Ted Huang Jack Hu
Julie Bauer Rick Chiu
Bob Rush Mike Kennedy
MingShang Kuo Tiffany Correl
Bill Pfund
Chandra Vemavarapu
Mayur Lodaya
Bill Polak

2008-5 AAPS 53