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

2

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

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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: 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

Hexamethylmelamine

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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

Phenytoin

Nokhodchi (2005)J Crystal Growth 274:573

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Crystal HabitsCrystal Habits

Nokhodchi (2005) J Crystal Growth 274:573

Carbamazepine

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Crystal HabitsCrystal Habits

12

Crystal HabitsCrystal Habits

paracetamol

Columnar

Plate-like

Prasad et al2002, Int J Pharm238:29

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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

paracetamol

Columnar

Plate-like

Prasad et al2002, Int J Pharm238:29

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Crystal HabitsCrystal Habits

Columnar Plate-like

Variation in strain content

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Crystal HabitsCrystal Habits

Heng et al (2006) Pharm Res 23: 1918

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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

Polymorphism

SulfamethoxydiazineForm II

Form III

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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