Through Vial Impedance Spectroscopy (TVIS) A novel process analytical technology for the development of freeze-drying processes and products Prof. Geoff Smith Leicester School of Pharmacy, De Montfort University, United Kingdom T hrough V ial I mpedance S pectroscopy
Outline • Introduction o Description of Measurement System o Theory (Dielectric loss mechanisms) • TVIS Applications o Ice Formation and phase separation in freezing Yowwares Jeeraruangrattana o Temperature calibration and prediction GPO Thailand o Drying rate estimation o Heat transfer coefficient calculation o End-point determination o Dry Layer resistance and collapse (time permitting) • Acknowledgements TVIS pass through on GEA Lyophil dryer, Hurth, Cologne T hrough V ial I mpedance S pectroscopy 2
Introduction to the TVIS System • Impedance spectroscopy characterizes the ability of materials to conduct electricity under an applied an oscillating voltage (of varying frequency) • Impedance measurements across a vial rather than within the vial • Hence “ Through Vial Impedance Spectroscopy” • Features • Single vial “non - product invasive” • Both freezing and drying characterised in a single technique • Non-perturbing to the packing of vials • Stopper mechanism unaffected T hrough V ial I mpedance S pectroscopy 3
Through Vial Impedance Spectroscopy (TVIS) Description of Measurement System T hrough V ial I mpedance S pectroscopy 4
Freeze drying chamber Junction Pass-through box Resultant Stimulating current voltage TVIS measurement vial LyoView TM analysis software TVIS system LyoDEA TM measurement software (I to V convertor) T hrough V ial I mpedance S pectroscopy 5
TVIS Measurement System • The designs of various vials that have been Adelphi Adelphi Adelphi modified with copper foil electrodes (10 mm in VC010-20C VC005-20C VCD005 height and 3 mm from the base of each container i. 20 mm crimp-neck vial with 10 ml nominal capacity ii. 20 mm crimp-neck vial with 5 ml nominal capacity iii. screw-neck vial with 5 ml nominal capacity A B • The different styles of a bespoke pass-through for TVIS systems A. Connected via the manifold hose on the outside of the dryer B. Connected via the port on top left side of the door on the dryer C C. Connected to a port on the top of the drying chamber T hrough V ial I mpedance S pectroscopy 6
Through Vial Impedance Spectroscopy (TVIS) Dielectric Loss Mechanisms T hrough V ial I mpedance S pectroscopy 7
1.1 1.1 22 mm mm mm + - + - + - Measurement vial + - + - + - + - + - + - Glass Glass + - + - + - 10 mm + - + - + - + - + - + - + - + - + - + - + - + - Electronic polarization Electronic polarization 𝐹 𝐹 distortion of electrons distortion of electrons H+ + + OH− relative to the nuclei - - relative to the nuclei OH− H+ Atomic polarization Atomic polarization H+ OH− OH− H+ distortion of nuclei across distortion of nuclei across - H+ + - + a heteroatom bond by a heteroatom bond by OH− stretching and bending stretching and bending Proton-hopping Instantaneous polarization dominant Instantaneous polarization dominant Conduction of protons in liquid water occurs mechanism in the glass wall mechanism in the glass wall through the Grotthuss "hop-turn" mechanism Conductivity in pure water Dipolar polarization δ + δ - re-orientation/alignment of permanent dipoles in liquid water (Debye-like δ + relaxation) Space charge polarization Space charge polarization (weak frequency dependence) (weak frequency dependence) Polarization mechanisms in liquid water MW (space-charge) polarization at glass (relaxation time, ~ 9 ps at 20 o C) MW (space-charge) polarization at glass wall – sample interface wall – sample interface TVIS response for empty vial TVIS response for empty vial TVIS response for liquid water 8
1.1 1.1 22 mm mm mm + - + - + - Measurement vial + - + - + - + - + - + - Glass Glass + - + - + - 10 mm + - + - + - + - + - + - + - + - + - + - + - + - Electronic polarization Dominant at T > 235 K (approx. −40 o C) Electronic polarization 𝐹 𝐹 distortion of electrons Generation/migration of L- and D- orientation defects distortion of electrons + + relative to the nuclei - in ice Ih - relative to the nuclei Atomic polarization Atomic polarization distortion of nuclei across distortion of nuclei across - + - + a heteroatom bond by a heteroatom bond by stretching and bending stretching and bending Instantaneous polarization dominant Instantaneous polarization dominant Dominant at T < 235 K (approx. −40 o C) mechanism in the glass wall mechanism in the glass wall Generation/migration of H3O+/OH− ion pairs (ionic defects) in ice Ih (similar to the Grotthus mechanism) Polarization mechanism in ice Space charge polarization Space charge polarization (weak frequency dependence) (weak frequency dependence) MW (space-charge) polarization at glass MW (space-charge) polarization at glass wall – sample interface wall – sample interface TVIS response for empty vial TVIS response for frozen water (ice) TVIS response for empty vial 9
Frozen Water and Dielectric Relaxation of Ice 3.0 Real part Capacitance 20.3 °C : The polarization of the water I. 2.5 dipole in liquid water at 20 ˚C , 2.0 with a dielectric loss peak C ′ / pF (II) -20 °C 1.5 -40 °C frequency of ~ 18 GHz 1.0 (III) (IV) : The Maxwell-Wagner (MW) (I) II. 0.5 polarization of the glass wall of 0.0 the TVIS vial at 20 ˚C, with a 1 2 3 4 5 6 7 8 9 10 11 12 13 Log Frequency dielectric loss peak frequency of 17.8 kHz Imaginary part Capacitance 0.8 18 kHz 20.3 °C 0.7 2.6 kHz III. : The dielectric polarization of ice -20 °C 0.6 537 Hz 18 GHz -40 °C at − 20 ˚C , with a dielectric loss 0.5 - C″ / pF peak frequencies of 2.57 kHz 0.4 0.3 0.2 IV. : The dielectric polarization of ice 0.1 at − 40 ˚C with a dielectric loss 0.0 peak frequencies of 537 Hz. 1 2 3 4 5 6 7 8 9 10 11 12 13 Log Frequency T hrough V ial I mpedance S pectroscopy 10
Through Vial Impedance Spectroscopy (TVIS) Applications T hrough V ial I mpedance S pectroscopy 11
Through Vial Impedance Spectroscopy (TVIS) 𝐺 Monitoring Phase Behaviour 𝑄𝐹𝐵𝐿 temperature calibration Surrogate drying rate ″ (ice nucleation temperature for predicting temperature of 𝑒𝐷 𝑄𝐹𝐵𝐿 (from ) 𝑒𝑢 and solidification end points the product in primary drying by using 𝐺 𝑄𝐹𝐵𝐿 Liquid State 0.8 0.6 0.8 Drying time C ″ PEAK Solid 0.5 -18 o C State 0.6 0.6 -C ″ / pF -C ″ /pF 0.4 - C ″ / pF increase -38 o C 0.4 0.4 0.3 0.2 0.2 0.2 0.1 0.0 0.0 0.0 F PEAK F PEAK 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 Log Frequency Log Frequency Log Frequency 𝐷 ′ (~ 100 kHz) is highly sensitive to low ice volumes; therefore it could be used for determination end point of primary drying T hrough V ial I mpedance S pectroscopy 12
TVIS Response Surface (3D-Plot) Imaginary Part of Capacitance Real Part of Capacitance Annealing = Re-heating and Re-cooling Liquid state Frozen solid Liquid state Re-heating Re-heating Re-cooling Frozen solid Re-cooling Primary drying Primary drying low frequency low frequency Intermediate frequency low frequency High frequency T hrough V ial I mpedance S pectroscopy 13
Phase Separation in Freezing Step 5%w/v Lactose solution (frozen) Water (frozen) Liquid state 0.5 1.0 Liquid state Unfrozen fraction peak 0.4 0.8 Ice peak - C″ / pF -C ″ / pF 0.3 0.6 0.2 0.4 Ice peak 0.1 0.2 0.0 0.0 1 2 3 4 5 6 1 2 3 4 5 6 Log Frequency Log Frequency 𝐷 𝑗𝑑𝑓 𝐷 𝑣𝑜𝑔𝑠𝑝𝑨𝑓𝑜 𝐷 𝐻 𝐷 𝑗𝑑𝑓 𝐷 𝐻 𝑆 𝑗𝑑𝑓 𝑆 𝑣𝑜𝑔𝑠𝑝𝑨𝑓𝑜 Unfrozen 𝑆 𝑗𝑑𝑓 Fraction ice Glass Wall Glass Wall Electrode Electrode Microstructure Microstructure T hrough V ial I mpedance S pectroscopy 14
Dielectric loss spectrum • Data analysing software (LyoView ™ ) 0.40 identifies the peak frequency ( 𝐺 𝑄𝐹𝐵𝐿 ) ″ and peak amplitude ( 𝐷 𝑄𝐹𝐵𝐿 ) in the imaginary part of the capacitance 0.30 ″ 𝐷 𝑄𝐹𝐵𝐿 spectrum - C″/pF 0.20 0.10 𝐺 𝑄𝐹𝐵𝐿 0.00 1 2 3 4 5 6 Log Frequency T hrough V ial I mpedance S pectroscopy 15
Through Vial Impedance Spectroscopy (TVIS) Temperature calibration & Temperature prediction T hrough V ial I mpedance S pectroscopy 16
Temperature Calibration 1.2 -41.5 °C -15.5 °C 1.0 0.8 - C″ / pF 0.6 0.4 -5 Shelf Temp. -10 0.2 Temperature / o C -15 𝑼 𝑼𝑫 𝟐 0.0 -20 1 2 3 4 5 6 -25 Log Frequency -30 𝑼 𝑼𝑫 𝟑 -35 -5 -40 y = -0.543x 2 + 26.718x - 108.5 -10 -45 R² = 0.9999 Temperature / o C -15 -50 Bottom electrode -20 6.0 6.5 7.0 7.5 8.0 -25 Time /h -30 Polynomial coefficient from 𝑀𝑝 𝐺 𝑄𝐹𝐵𝐿 − temperature calibration -35 -40 𝑏 𝑐 𝑑 y = -1.0225x 2 + 30.106x - 114.74 -45 R² = 0.9999 -50 -114 -1.02 30.1 TE 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 Log F PEAK -109 -5.43 x 10 -1 26.7 BE 17
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