Crystal structures and
morphology, factors affecting
solubility and dissolution
Hak Kim Chan
The University of Sydney
RACI Pharmaceutical Science Group Dissolution Workshop 26 Aug 2010
1
Dissolution Rate
Boundary
Diffusion
layer
Bulk Solution
concentration
Cs
Drug
C
h
dM
AD
( Cs – C)
=
dt
h
2
Dissolution Rate
dM
AD
( Cs – C)
=
dt
h
Factors affecting Dissolution Rate
A – Surface Area of the dissolving solid
D – Diffusion Coefficient of drug in the medium
h – Boundary layer (Diffusion layer, stagnant layer)
Cs – Saturated concentration (solubility) of drug
C – Bulk concentration of drug
(Cs – C) / h – Concentration gradient
3
Factors Affecting Dissolution Rate
dM
AD
( Cs – C)
=
dt
h
A – Surface Area of the dissolving solid
1. Particle size: surface area
2. Which surface? crystal shape (habit)
3. Wetting of the surface
4
Factors Affecting Dissolution Rate
dM
AD
( Cs – C)
=
dt
h
A – Surface Area of the dissolving solid
Particle size: surface area  diameter 2
specific surface area  1 / diameter
Heng et al (2008)
Pharm Res
25: 1696
1 µm
Cefuroxime Axetil
5
Factors Affecting Dissolution Rate
dM
AD
( Cs – C)
=
dt
h
A – Surface Area of the dissolving solid
1. Particle size
2. Which surface? crystal shape (habit)
6
Crystal Habits
Hexamethylmelamine
7
Crystal Habits
RL
2.10
RW
1.40
mm/s 0.70
0.00
0.00
0.20
Rodley et al (1993) Int J Pharm 95: 143
0.40
0.60
0.80
1.00
mm/s
8
Phenytoin
Nokhodchi (2005)
J Crystal Growth 274:573
Crystal Habits
Carbamazepine
Nokhodchi (2005) J Crystal Growth 274:573
10
Crystal Habits
11
Crystal Habits
paracetamol
Columnar
Plate-like
Prasad et al
2002, Int J Pharm
238:29
12
Crystal Habits
Dissolution Etch Patterns
{001} face
{110} face
Prasad et al (2002) Int J Pharm 238: 29
13
Crystal Habits
paracetamol
Columnar
Plate-like
Prasad et al
2002, Int J Pharm
238:29
14
Crystal Habits
Variation in strain content
Columnar
Plate-like
15
Crystal Habits
Heng et al (2006) Pharm Res 23: 1918
16
Crystal Habits
Contact Angle with H2O (degree)
(011)
(010)
29.8
67.7
Surface Energy (mJ/m2)
(011)
(010)
Dispersive Polar
33.9
32.7
45.1
7.0
Heng et al (2006) Pharm Res 23: 1918
17
Impurities or Habits?
(a)
(b)
(c)
(d)
Chow et al (1985) Int J Pharm 24: 239
(e)
(f)
18
Mass dissolved (mg)
Intrinsic dissolution rate
Time (min)
Chan & Grant (1989) Int J Pharm 57: 117
19
Factors Affecting Dissolution Rate
dM
AD
( Cs – C)
=
dt
h
A – Surface Area of the dissolving solid
1. Particle size
2. Surface: crystal shape (habit)
3. Wetting of the surface
20
Instrinsic Dissolution Rate Ratio
Particle Surface Wetting
Surface Tension mN/m
Chow et al (1995) Int J Pharm 126:21
21
Factors Affecting Dissolution Rate
dM
AD
( Cs – C)
=
dt
h
D – Diffusion coefficient of the drug
kT
D =
6r
K – Boltzmann constant
T – temperature
- viscosity of the medium
r – radius of the drug molecule
22
Factors Affecting Dissolution Rate
dM
AD
( Cs – C)
=
dt
h
h – Boundary layer thickness
Particle size: h  diameter
Environmental: stirring, temperature, viscosity
23
Factors Affecting Dissolution Rate
dM
AD
( Cs – C)
=
dt
h
Cs – saturated conc’n
(solubility)
Solid forms
• Polymorphism
C – bulk concentration
• Amount of drug dissolved
• Volume of dissolution
medium
• Solvates > non-solvate
• Anhydrate > hydrate
• Amorphous > crystalline
24
Solid Forms
Amorphous > Crystalline
Calcium Fenoprofen
Hendriksen (1990)
Int J Pharm 60:243
25
Solid Forms
Polymorphism
Iopanoic acid
Form II
Form I
Stagner & Guillory (1979) J Pharm Sci 68, 1005
26
Solid Forms
Polymorphism
Sulfamethoxydiazine
Form II
Form III
27
Solid Forms
Anhydrate > Hydrate
Oxyphenbutazone
Anhydrate
Hemihydrate
Monohydrate
Stoltz et al (1988)
J Pharm Sci 77:1047
28
Conclusions
dM
AD
( Cs – C)
=
dt
h
A – particle size and shape
D – temperature, viscosity
h – stirring, temperature, viscosity
(Cs – C) – crystal forms, polymorphism, solvate
Confounding factors
• Small particles  Agglomeration  Area reduced
• Solid forms, wetting, crystal defects, impurities
• Single crystals  Powder  Formulation
Compact
29