crystal structures and morphology, factors affecting
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1
Crystal structures andmorphology, factors affecting
solubility and dissolution
Hak Kim Chan
The University of Sydney
RACI Pharmaceutical Science Group Dissolution Workshop 26 Aug 2010
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Dissolution RateDissolution Rate
d t h=
dM A D( Cs – C)
co
nce
ntr
atio
n
Drug
Cs
C
h
BoundaryDiffusionlayer
Bulk Solution
3
Dissolution RateDissolution Rate
d t h=
dM A D( Cs – C)
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
4
Factors Affecting Dissolution RateFactors Affecting Dissolution Rate
d t h=
dM A D( Cs – C)
A – Surface Area of the dissolving solid
1. Particle size: surface area
2. Which surface?
3. Wetting of the surface
crystal shape (habit)
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Factors Affecting Dissolution RateFactors Affecting Dissolution Rate
d t h=
dM A D( Cs – C)
A – Surface Area of the dissolving solid
Particle size: surface area diameter 2
specific surface area 1 / diameter
Cefuroxime Axetil1 µm
Heng et al (2008)Pharm Res25: 1696
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Factors Affecting Dissolution RateFactors Affecting Dissolution Rate
d t h=
dM A D( Cs – C)
A – Surface Area of the dissolving solid
1. Particle size
2. Which surface? crystal shape (habit)
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Crystal HabitsCrystal Habits
0.00 0.20 1.000.800.600.40
0.00
0.70
1.40
2.10
RL
RW
Rodley et al (1993) Int J Pharm 95: 143
mm/s
mm/s
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Crystal HabitsCrystal Habits
{001} face {110} face
Dissolution Etch Patterns
Prasad et al (2002) Int J Pharm 238: 29
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Crystal HabitsCrystal Habits
Contact Angle with H2O (degree)
(011) 29.8(010) 67.7
Surface Energy (mJ/m2)
Dispersive Polar(011) 33.9 32.7(010) 45.1 7.0
Heng et al (2006) Pharm Res 23: 1918
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Impurities or Habits?Impurities or Habits?
(a) (b)
(f)(e)
(d)(c)
Chow et al (1985) Int J Pharm 24: 239
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Intrinsic dissolution rateIntrinsic dissolution rate
Time (min)
Ma
ss
dis
so
lve
d(m
g)
Chan & Grant (1989) Int J Pharm 57: 117
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Factors Affecting Dissolution RateFactors Affecting Dissolution Rate
d t h=
dM A D( Cs – C)
A – Surface Area of the dissolving solid
1. Particle size
2. Surface: crystal shape (habit)
3. Wetting of the surface
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Particle Surface WettingParticle Surface Wetting
Surface Tension mN/m
Inst
rin
sic
Dis
solu
tion
Ra
teR
atio
Chow et al (1995) Int J Pharm 126:21
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Factors Affecting Dissolution RateFactors Affecting Dissolution Rate
d t h=
dM A D( Cs – C)
D – Diffusion coefficient of the drug
6 r=D
k T
K – Boltzmann constantT – temperature- viscosity of the mediumr – radius of the drug molecule
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Factors Affecting Dissolution RateFactors Affecting Dissolution Rate
d t h=
dM A D( Cs – C)
h – Boundary layer thickness
Particle size: h diameter
Environmental: stirring, temperature, viscosity
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Factors Affecting Dissolution RateFactors Affecting Dissolution Rate
d t h=
dM A D( Cs – C)
Cs – saturated conc’n(solubility)
Solid forms
• Polymorphism
• Solvates > non-solvate
• Anhydrate > hydrate
• Amorphous > crystalline
C – bulk concentration
• Amount of drug dissolved
• Volume of dissolution
medium
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Solid FormsSolid Forms
Amorphous > Crystalline
Calcium FenoprofenHendriksen (1990)Int J Pharm 60:243
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Solid FormsSolid Forms
Polymorphism
Iopanoic acidForm II
Form I
Stagner & Guillory (1979) J Pharm Sci 68, 1005
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Solid FormsSolid Forms
Anhydrate > Hydrate OxyphenbutazoneAnhydrate
Hemihydrate
Monohydrate
Stoltz et al (1988)J Pharm Sci 77:1047
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ConclusionsConclusions
d t h=
dM A D( Cs – C)
A – particle size and shapeD – temperature, viscosityh – 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
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