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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. Young Innovators 2009 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. Young Innovators 2009 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