Research Achievement Winner Lecture
AAPS Annual Meeting 2010
Formulation of Poorly Water-Soluble Drugs:
Drug Delivery Strategies
Abu T. M. Serajuddin, Ph.D.
St. John’s University, Queens, New York
E-mail: serajuda@stjohns.edu; Phone: 718-990-7822
Recent Trends in New Molecule Solubility
50
Two-thirds (?):
Insoluble or
Practically
Insoluble
Very slightly
soluble or
soluble
Percent
40
30
20
New
Generation
10
0
<10µg/mL
10-100µg/mL
>100µg/mL
Solubility
Solubility < 1 μg/mL (0.001 mg/mL) is common
2
Source: Personal experience, literature data and anecdotal information
Dosage Form Development Strategies
A few common strategies to overcome
impacts of low solubility on product
development:
–
Particle size reduction
•
•
–
–
–
–
Milling
Nanosizing
Salt formation
Solubilization
Solid dispersion
Lipid-based drug delivery
To save time and resources in product
development, relatively simpler
approaches should be tried first.
3
Salt Formation
How Does Salt Formation Increase
Dissolution Rate?
J = dM = DA (Cs - C )
dt
h
Diffusion Layer Model
Cs, h=0 >> Cs, bulk medium
…. by changing
microenvironmental
pH and solubility
Bulk Liquid
Phase
Solid
(salt)
•Saturate
•Supersaturate,
and/or
•Fine precipitate
(Dissolution Medium)
Stagnant
Diffusion
Layer
h
5
C
Effect of Salt Formation on Drug Solubility
pH-Solubility Profile of Haloperidol Mesylate,
Hydrochloride and Phosphate
100000
30 mg/mL
Line: fitted by equation
Log Solubility (µg/mL)
Mesylate
HCl
1000
Phosphate
10
Mesylate > HCl > Phosphate
2.5 µg/mL
0.1
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14
pH
6
Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin.
Investigation of Solubility and Dissolution of a Free Base and Two Different Salt
Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)
Dissolution Profiles of a Free Base
Cumulative amount released
(mg)
Intrinsic dissolution of haloperidol base
35
pH 2.05
30
25
20
15
10
pH 3.08
pH 1.1
5
pH 5.0
0
0
15
30
45
60
75
Time (min)
90
105 120
Solubility is practically zero under intestinal pH conditions (5 and higher)
7
Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and
Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)
Dissolution Rates of Salt Forms of a
Basic Compound
Intrinsic dissolution of haloperidol hydrochloride
Intrinsic dissolution of haloperidol mesylate
300
40
pH 3.08
30
25
pH 7.0
20
pH 2.02
15
10
pH 3.05
250
pH 5.02
Cumulative amount released (mg)
Cumulative amount released (mg)
35
pH 5.01
pH 7.0
200
150
pH 2.08
100
50
5
pH 1.1
0
0
0
15
30
45
60
75
Time (min)
8
pH 1.65
pH 1.08
90
105 120
0
15
30
45
60
75
90
105 120
Time (min)
Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and
Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)
Limitation of
Salt Formation
Limitation of Salt Formation for the New
Generation of Poorly Water-soluble Drugs
Diffusion Layer Model
When the intrinsic
solubility is very low, the
precipitated free base
coats the dissolving
surface, preventing
further dissolution of salt.
Solid
(salt)
Precipitated Free Base
Please note: Precipitation
at the surface, not in the
bulk medium. No increase
in surface area.
X
Cs, h=0 >> Cs, bulk medium
Bulk Liquid
Phase
X
(Dissolution Medium)
Stagnant
Diffusion
Layer
C
h
10
High-energy Solid
11
Structure of High-energy Solids
liquid
(enthalpy, H)
Heat content
High-energy amorphous
solid
Crystal
12
Temperature
Low-energy
crystalline solid
Solid Dispersion
13
Storage temperature
(enthalpy, H)
Heat content
Advantage of Solid Dispersion: Better
Stability than Purely Amorphous System
Drug only
Drug - polymer
miscible blend
Elevated Tg
Tg (drug)
14
Temperature
Tg (mixture)
What is Solid Dispersion ?
“the dispersion of one or more active ingredients in an inert carrier or matrix,
where the active ingredients could exist in finely crystalline, solubilized or
amorphous state” - Chiou and Riegelman, J Pharm Sci 1971, 60, 1281-1302
Drug
(crystalline)
No miscibility
Carrier
+
Partial miscibility
(amorphous)
Complete miscibility
Advantage of Solid Dispersion:
Higher Dissolution Rate
Poorly Water-Soluble Drug
Tablet/Capsule
Solid Dispersion
Dosage Form
Disintegration
Large Solid Particles
(Usually 5-100 microns)
Lower Dissolution
Rate
16
Matrix Dissolves
Drug in G.I.
Tract
Colloidal Drug
Particles/Globules
Absorption
into Body Systems
Higher Dissolution
Rate
Ref: Serajuddin, J. Pharm. Sci. 1999, 88, 1058
Surfactant-based
Solid Dispersions
Solid Dispersion by Melt-Filling:
Advantage of Surfactant
Aqueous Dispersion of Solid Plug
Solid dispersion
Disintegration of
capsule shell
Solid Plug
with Layer
Solid Plug
Non-Surface active vehicle
18
• Forms drug-rich surface layer
Surface active vehicle
• Retards/prevents dissolution
of drug
• Rapid dissolution rate
• Disperses/emulsifies drug
Development of Solid Dispersion:
Compound A
Composition of Solid Dispersion
Prepared
Compound A (LAB687)
20 mg
Polysorbate 80
0-120 mg
PEG 3350
360-0 mg
Total Weight
500 mg
Capsule size # 0
Ref:
19
Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004)
Solid Dispersion Selected for Clinical
Study: Compound A
Composition of Solid Dispersion
Compound A
20 mg
Polysorbate 80
120 mg
PEG 3350
360 mg
Capsule size # 0
Ref:
20
Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004)
Bioavailability in Dogs from Solid
Dispersion: Compound A
Formulation
AUC (0-48h)
(ng.h/mL)
Solid dispersion
6960
Solubilized system
6900
Capsule (mic. Powder)
Ref:
21
681
Relative
Bioavailability
100
100
10
Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004)
Solid Dispersion by
Melt Extrusion
22
Solid Dispersion by Melt Extrusion
Technology
Melt extrusion is a single-step process ideally suitable
to manufacture solid dispersion
Homogeneous mixture of active, polymer
plasticizer, surfactant
Ref: Adapted from J. Kowalski (Novartis) presentation
23
Crystalline drug subs.
+
Polymer
Amorphous drug subs.
+
Polymer
High
temperature
melt extrusion
Lower
temperature
melt extrusion
Amorph. extrudate
Lower Temperature Melt Extrusion – A
Novel Strategy
Drug
degradation
Stable product
Ref: Lakshman et al., Molecular Pharmaceutics, 5:994-1002, 2008
24
Microemulsion
25
What is Microemulsion? -‘Cyclosporine A’
Example
Without
dilution
Cyclosporin A
Sandimmune®
Neoral®
20 – 150 nm
( < 200 nm)
Microemulsion
(o/w)
Dilution
with
water
Ref:A. Meinzer et al,
BT Gattefosse 88 :21-26, 1995
26
Systematic Screening of Lipids for
Microemulsion Formation
Structures of Lipids
C8 Chain fatty acid
Glyceryl Caprylate/Caprate
(Capmul MCM; ABITEC Co.)
Glyceryl Dicaprylate
(ABITEC Co.)
Glyceryl Tricaprylate
(Captex 8000; ABITEC Co.)
Ternary System for Monoglyceride (Glyceryl
Caprylate/Caprate), Cremophor EL and Water
Oil : Surfactant
%
Water
Gel
9:1
7:3
5:5
3:7
2:8 1:9
Particle Size, nm
70
4815 7865 1215 2481
28
15
80
7126 3859 1532 1265
18
12
90
1609 3242
743
473
15
12
99
2978 1173
578
430
15
14
Ternary System for Diglyceride( Glyceryl
Dicaprylate), Cremophor EL and Water
Oil : Surfactant
%
9:1
7:3
Water
5:5
3:7
2:8
1:9
Particle Size, nm
70
2788
492
90
17
80
32
80
2007
286
55
20
77
14
90
1844
222
35
18
19
14
99
1903
153
35
20
19
16
Ternary System for Triglyceride (Caprylate/
Caprate Triglyceride), Cremophor EL and Water
Oil : Surfactant
%
9:1
Water
7:3
5:5
3:7
2:8
1:9
Particle Size, nm
70
1580
619
1296
533
867
116
80
1794
463
634
390
685
39
90
2136
380
383
334
402
22
99
3851
291
218
172
154
20
Pseudo-Ternary System using 1:1-Tri- + MonoGlycerides, Cremophor EL and Water
Oil : Surfactant
%
9:1
7:3
Water
6:4
5:5
4:6
3:7 2:8 1:9
Particle Size, nm
70
3353
1105
115
43
22
20
18
24
80
5303
395
153
21
17
15
14
33
90
875
546
44
21
17
16
14
16
99
338
41
30
25
20
18
16
16
Pseudo-Ternary System using 1:1-Di- + MonoGlycerides, Cremophor EL and Water
Oil : Surfactant
7:3
%
5:5
3:7
2:8
1:9
Particle Size, nm
Water
70
1029 1079
150
82
80
80
1063
442
22
18
17
90
870
252
18
16
17
99
50
78
20
16
16
Solid Microemulsion Preconcentrate
- A Novel Solid Dispersion
34
Solid Microemulsion Preconcentrate
Solid dispersion
Solid preconcenrate
Liquid
preconcentrate
Component
CF 3
Solid Microemulsion
Preconcentrate
O
O
H 3C
N
H
N
H
O
CH 3
Compound A
35
Compound A (%w/w)
4
8
Capmul PG8 (%w/w)
28.8
27.6
Cremophor EL
(%w/w)
28.8
27.6
PEG 3350 (%)
38.4
36.8
Ref: Li et al., J. Pharm. Sci., 98:1750-1763, 2009
Formulation of Poorly Water-Soluble
Drugs
Concluding Remarks
 Almost one-third of compounds synthesized
by discovery scientists is extremely waterinsoluble (solubility in water: <10 µg/mL)
 Conventional formulation techniques may no
longer be applicable to most, if not all, of
them.
 Special formulation approaches are
necessary to enable development of such
compounds.
 Formulation strategies must be selected
based on dose, solubility and other
physicochemical properties of NCEs.
36