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

Young Innovators 2009

• 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.

Temperature, Pressure, Surrounding vapors etc.

Hydrate

Anhydrate

DryingDehydration

Temperature, Pressure, Surrounding vapors etc.

Hydrate

Anhydrate

DryingDehydration

RESEARCH OBJECTIVES

Young Innovators 2009

• To elucidate the solid-state transformation of a model hydrate.

• To establish the causal relationship between dehydration behaviors and key operating parameters.

Packing structure

Crystal size/habit Polymorphism/solvation

Moisture stability

Drying & dehydration

Thermodynamic aspect

XR

D In

tens

ity

2-Theta (º)

-15000

-10000

-5000

0

5000

10000

15000

20000

25000

5 10 15 20 25 30

5000

10000

15000

20000

25000

5 10 15 20 25 30

0

10000

20000

30000

40000

50000

60000

70000

80000

5 10 15 20 25 3045000

55000

5 10 15 20 25 30

Fre

e en

ergy

Structure

ΔG1*ΔG2

*ΔG3

*ΔG4

*

ΔG

Kinetic aspect

Mas

s ch

ange

Time

α

t

α

α

α

t

t t

Loose crystal

180-250μm

250-500μm

500-710μm

710-1400μm

>1400μmLoose crystal

180-250μm

250-500μm

500-710μm

710-1400μm

>1400μmLoose crystal

180-250μm

250-500μm

500-710μm

710-1400μm

>1400μm

Bound vs. Unbound

RESEARCH OUTCOME

Stability increases at ambient condition.

Dihydrate Agglomerates

Atmospheric & low pressure dehydration

Reduced pressure10-3 to 102 Torr

Humidity 5% to 60% RH

Organic solvent(Acetone, EtOH & MeOH)

5% to 90% P/P0

CBZTriclinic

CBZC-monoclinic

CBZP-monoclinic

Dihydrate Loose crystals

Atmospheric pressure

CatastrophicNo accessibility

of vaporWater vapor-

mediatedSolvent vapor-

mediated

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MATERIALS & METHODS

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500μm

Needle shaped DH

500μm

Plate shaped DH

Crystallisation2‘Forced’ hydration 1

400μm

Agglomerated DH

Moi

stur

e c

ont

en

t, X

A

Dehydration time

20ºC to 50ºC

Dehydration kinetics• Activation energy determination

2-Theta (º)Stru

ctura

lD

iffra

ctio

n in

tens

ity

Dehydration stability• Monitor phase transformation

• Dynamic Vapour Sorption• X-ray powder diffraction• TGA, DSC;• SEM, HSM;• N2 BET, Hg Porosimetry.

DEHYDRATION STABILITY

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‘Smooth’ dehydration• Dehydration rate α solubility:

MeOH > EtOH > Acetone >> Water.

• Rate limiting diffusion of water.

-15000

-10000

-5000

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20000

30000

40000

50000

60000

70000

80000

5 10 15 20 25 3045000

55000

5 10 15 20 25 305 10 15 20 25 30

Dif

frac

tio

n in

ten

sity

(a.

u.)

2-Theta (º)

20000

30000

40000

50000

60000

5 10 15 20 25 30

45000

55000

5 10 15 20 25 30

0

10000

20000

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60000

70000

80000

5 10 15 20 25 3045000

55000

5 10 15 20 25 305 10 15 20 25 30D

iffr

acti

on

inte

nsi

ty (

a.u

.)2-Theta (º)

‘Catastrophic’ dehydration• Collapse to amorphous form.• Recrystallisation on different

facets.• Rate limiting nucleation.

Dehydration at MeOH %P/P0, 20ºC. Dehydration at 10-3 Torr, no air flow.

Dehydrating

Organic solvent vapor induced

Water vapor induced

Vacuum pressure induced

CONCLUSIONS

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• 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.

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)

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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 MSENovember 10th, 2009. From 0830 to 1100, Room 502A.

• AAPS 2009 Poster No.: W5368November 11th, 2009. From 1300 to 1700, West Exhibit Hall A.

Young Innovators 2009

CONTACT INFO

Young Innovators 2009

Ji Yi Khoo

Email: j.khoo06@imperial.ac.uk

Website: www.imperial.ac.uk/spel

Department of Chemical Engineering

Imperial College London

South Kensington Campus

London SW7 2AZ

United Kigndom.