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YOUNG INNOVATORS 2009
Pharmaceutical Channel Hydrate:
Elucidation of its Thermodynamic Stability and
Solid-state Transformation during Dehydration.
Ji Yi Khoo, J. Y. Y. Heng & D. R. Williams
Department of Chemical Engineering,
Imperial College London, United Kingdom.
DRYING: NEMESIS OF HYDRATE
Drying
Dehydration
Hydrate
Anhydrate
Temperature, Pressure, Surrounding vapors etc.
• 50% of hydrate-forming drug substances used in hydrate form.
• Drying: Controls the processability, quality and marketability.
• Problem: caking/agglomeration, lump formation, decrease in
purity, irreversible damage - polymorphism.
Young Innovators 2009
RESEARCH OBJECTIVES
• To elucidate the solid-state transformation of a model hydrate.
• To establish the causal relationship between dehydration
behaviors and key operating parameters.
Drying & dehydration
Kinetic aspect
Bound vs. Unbound
α
Mass change
α
α
t
se
Loo
t
l
sta
0μ m
cry
0μm
-25
0μm
m
-50
m
180
-71
00μ
250
00μ
500
-14
>14
710
Thermodynamic aspect
Moisture stability
DH 90%MeOH 30mins
XRD Intensity
25000
20000
25000
24 hours
20000
15000
80000
Relative
intensity
(counts)
Relative
intensity
(counts)
15000
70000
10000
10000
60000
5000
5000
50000
55000
5
10
15
20
25
30
10
15
20
25
30
15
20
15 2-Theta 20
2-Theta
25
25
30
30
0
40000
-5000
30000
-10000
20000
-15000
10000
5
0
45000 5
5
10
10
2-Theta (º)
Polymorphism/solvation
t
t
Time
Packing structure
α
Free energy
Crystal size/habit
ΔG1* ΔG2*
ΔG3* ΔG *
4
ΔG
Structure
Young Innovators 2009
RESEARCH OUTCOME
Dihydrate
Loose crystals
Dihydrate
Agglomerates
Atmospheric pressure
Atmospheric &
low pressure
dehydration
Organic solvent
(Acetone, EtOH & MeOH)
5% to 90% P/P0
Humidity
5% to 60% RH
Reduced pressure
10-3 to 102 Torr
Water vapormediated
Catastrophic
No accessibility
of vapor
CBZ
CBZ
CBZ
P-monoclinic
Triclinic
C-monoclinic
Solvent vapormediated
Stability increases at
ambient condition.
Young Innovators 2009
MATERIALS & METHODS
1 ‘Forced’ hydration
2 Crystallisation
Agglomerated
DH
Needle shaped
DH
Plate shaped
DH
400μm
500μm
500μm
Dehydration stability
• Activation energy determination
• Monitor phase transformation
20ºC to 50ºC
Dehydration time
•
•
•
•
•
DH crystal
1 hour
4 hours
8 hours
24 hours
Dynamic Vapour Sorption
X-ray powder diffraction
TGA, DSC;
SEM, HSM;
N2 BET, Hg Porosimetry.
Diffraction intensity
Moisture content, XA
Dehydration kinetics
2-Theta (º)
Young Innovators 2009
ru
St
l
ra
u
t
c
DEHYDRATION STABILITY
24 hours
DH 90%MeOH 30mins
24 hours
20000
15000
80000
Relative
intensity
(counts)
Relative
intensity
(counts)
15000
70000
10000
10000
60000
5000
5000
55000
50000 5
10
15
20
25
30
0
40000
-5000
30000
-10000
20000
-15000
10000
0
45000
5
5
55
10
10
10
10
15
15
15
15
20
20
20
2-Theta 20
2-Theta
25
25
25
25
30
30
30
30
2-Theta (º)
Dehydration at MeOH %P/P0, 20ºC.
60000
55000
Diffraction intensity (a.u.)
Diffraction intensity (a.u.)
20000
25000
Relative
Relative
intensity
intensity (counts)
(counts)
Relative
intensity
(counts)
Relative
intensity
(counts)
25000
24 hours
50000
80000
70000
60000
40000
55000
50000
45000
40000
30000 5
30000
20000
20000
10000
0
45000
5
Dehydrating
10
15
20
25
30
20
25
30
2-Theta
10
15
2-Theta
55
5
10
10
10
15
15
15
20
20
2-Theta 20
2-Theta
25
25
25
30
30
30
2-Theta (º)
Dehydration at 10-3 Torr, no air flow.
‘Smooth’ dehydration
‘Catastrophic’ dehydration
• Dehydration rate α solubility:
MeOH > EtOH > Acetone >>
Water.
• Collapse to amorphous form.
• Recrystallisation on different
facets.
Organic solvent vapor induced
Water vapor induced
• Rate limiting diffusion of water. • Rate limiting nucleation.
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Vacuum pressure induced
CONCLUSIONS
• Affinity & accessibility of solvent vapour pressure promotes
dehydration rate and determines formation of the end products.
• Potential to anticipate & tailor polymorphism in formulation
design & development of drug product.
• Inclusion of unbound water in agglomerated DH provides
strategy for improving moisture stability of formulated
products.
• As an experimental screening method for mapping out stability
envelope of other hydrating APIs.
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ACKNOWLEDGMENTS
• Academic Supervisors:
 Dr. Daryl R. Williams
 Dr. Jerry Y. Y. Heng
• All members of Surfaces and Particle Engineering Lab,
Imperial College London.
• Financial Supports:
 Overseas Research Studentships (ORS)
 Imperial College Student Opportunities Fund (SOF)
Young Innovators 2009
REFERENCES
• Khoo, J., Heng, J.Y.Y. & Williams, D.R. (2009) Agglomeration effects on
the drying and dehydration stability of a pharmaceutical acicular hydrate:
Carbamazepine dihydrate. Ind. & Eng. Chem. Res. (Accepted).
• Khoo, J., Heng, J.Y.Y. & Williams, D.R. (2009) Dehydration kinetics of
pharmaceutical hydrate: Effect of crystal properties. Proceedings of 4th
Inter-American Drying Conference. In: 8th World Congress of Chemical
Engineering, Montreal, Canada. II-21, p244-250.
• AAPS Graduate Student Symposium in MSE
November 10th, 2009. From 0830 to 1100, Room 502A.
• AAPS 2009 Poster No.: W5368
November 11th, 2009. From 1300 to 1700, West Exhibit Hall A.
Young Innovators 2009
CONTACT INFO
Ji Yi Khoo
Email: [email protected]
Website: www.imperial.ac.uk/spel
Department of Chemical Engineering
Imperial College London
South Kensington Campus
London SW7 2AZ
United Kigndom.
Young Innovators 2009