www.dmu.ac.uk/tvis Through-Vial Impedance Spectroscopy (TVIS) A novel process analytical technology for the development of pharmaceutical products and processes Vienna, Austria May 24 24 – 25 25, , 2018 PROF. GEOFF SMITH Professor of Pharmaceutical Process Analytical Technology Leicester School of Pharmacy De Montfort University, Leicester, UK
Outline • Description of TVIS measurement system • Applications in Brief • First time report on the use of dual-electrode system and its applications Ice region specific temperature prediction ( 𝑈 𝑗 , 𝑈 𝑐 ) Drying rate determination Heat transfer coefficient ( 𝐿 𝑤 ) determination • Acknowledgements • TVIS dielectric loss mechanisms T hrough V ial I mpedance S pectroscopy 2
Through Vial Impedance Spectroscopy (TVIS) Description of Measurement System T hrough V ial I mpedance S pectroscopy 3
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 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
Through Vial Impedance Spectroscopy (TVIS) Applications T hrough V ial I mpedance S pectroscopy 6
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 7
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 8
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 9
Through Vial Impedance Spectroscopy (TVIS) Dual-electrode system and its applications (Ice temperature, Drying rate and Heat transfer coefficient ) T hrough V ial I mpedance S pectroscopy 10
Dual-electrode system New feature of TVIS vial Standard TVIS vial (Single electrode system) (Dual electrode system) ~3.4 g of water ~8 g of water (∅ = 𝟏. 𝟖) (∅ = 𝟏. 𝟖) Top electrode height ~15 mm Electrode height ~10 mm Gap between electrode ~3 mm Bottom electrode height ~10 mm Electrode distance from base Electrode distance from base ~3 mm ~3 mm Electrode Dimension Electrode Dimension 10 x 19 mm Top electrode (TE): 10 x 19 mm Bottom Electrode (BE): 5 x 19 mm • A dual electrode system comprises two pairs of copper electrode glued to the external surface of a Type I tubular glass vial. • This option is suitable for large volume samples, including those used for 𝐿 𝑤 determination. T hrough V ial I mpedance S pectroscopy 11
Temperature Determination • 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝑈𝐹 : TVIS predicted temperature from top electrode (TE) Dual electrode • 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝐶𝐹 : TVIS predicted temperature from bottom electrode (BE) 𝑈 𝑗 Both 𝑈 𝑗 and 𝑈 𝑐 can be estimated by 15 x 19 mm 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝑈𝐹 extrapolating from the temperatures predicted from the centers of top 3 mm gap 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝐶𝐹 electrode ( 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝑈𝐹 ) and bottom 5 x 19 mm 𝑈 𝑐 electrode ( 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝐶𝐹 ). 3 mm gap T hrough V ial I mpedance S pectroscopy 12
Aims & Objectives Temperature calibration of log 𝐺 𝑄𝐹𝐵𝐿 of top electrode ( 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝑈𝐹 ) and I bottom electrode ( 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝐶𝐹 ) Prediction ice temperatures for both electrodes during primary II drying ″ Temperature calibration of 𝐷 𝑄𝐹𝐵𝐿 III Aims ″ Compensation of 𝐷 𝑄𝐹𝐵𝐿 IV during primary drying To determine the heat transfer coefficient ( 𝐿 𝑤 ) ″ Calibration of 𝐷 𝑄𝐹𝐵𝐿 V for ice layer height by using a novel dual electrode TVIS approach VI Estimation of ice layer height during primary drying Prediction ice temperatures at (i) sublimation interface ( 𝑈 𝑗 ) and (ii) VII vial’s base ( 𝑈 𝑐 ) including qualification TVIS technique ( 𝑈 𝑗 = 𝑈 𝑄 𝑗 =𝑄 𝑑 ) Comparison of TVIS drying rate ( ∆𝑛 ∆𝑢 ) with gravimetric VIII method (weight loss) Determination (i) the drying rate ( ∆𝑛 ∆𝑢 ) and (ii) ice base IX temperature ( 𝑈 𝑐 ) during the steady state period Heat transfer coefficient ( 𝐿 𝑤 ) calculation X 13
Temperature calibration of log 𝐺 𝑄𝐹𝐵𝐿 of top electrode Objective I ( 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝑈𝐹 ) and bottom electrode ( 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝐶𝐹 ) Identifying peak Calibration plot Predicting product frequency ( 𝐺 Annealing the In-line TVIS 𝑄𝐹𝐵𝐿 ) (temperature vs temperature using sample measurement using LyoView ™ Log 𝐺 𝑄𝐹𝐵𝐿 ) calibration plot software 14
Temperature calibration of log 𝐺 𝑄𝐹𝐵𝐿 of top electrode Objective I ( 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝑈𝐹 ) and bottom electrode ( 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝐶𝐹 ) Top electrode 1.2 -41.5 °C -25 °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 Top electrode -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 15
Prediction ice temperatures for both electrodes during Objective II primary drying 16
Prediction ice temperatures for both electrodes during Objective II primary drying Temp. constant Temp. constant 5 -28 0 Shelf Temperature (𝑈 𝑡 ) -5 -30 𝑈 𝑈𝐷 1 Temperature / o C Temperature / o C 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝐶𝐹 -10 𝑈 𝑈𝐷 2 -15 -32 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝑈𝐹 -20 𝑈 (𝑄 𝑗 =𝑄 𝐷@270𝜈𝑐𝑏𝑠 ) = −33.2 ℃ -25 -34 𝑈 𝑈𝐷 2 𝑈 𝑈𝐷 1 -30 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝐶𝐹 𝑈 𝐺 𝑄𝐹𝐵𝐿 𝑈𝐹 -35 -36 -40 -45 -38 0 1 2 3 4 5 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 Time / h Time / h The product temperature predicted by TVIS can demonstrate the temperature gradient across ice cylinder height 17
″ Temperature calibration of 𝐷 𝑄𝐹𝐵𝐿 Objective III Identifying peak Temperature Calibration plot ″ amplitude ( 𝐷 𝑄𝐹𝐵𝐿 Annealing the In-line TVIS ) compensation of ″ ( 𝐷 𝑄𝐹𝐵𝐿 vs ″ 𝐷 𝑄𝐹𝐵𝐿 sample measurement using LyoView ™ using temperature) software calibration plot 18
Objective ″ Temperature calibration of 𝐷 𝑄𝐹𝐵𝐿 III Top electrode 1.2 -41.5 °C -25.5 °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 1.00 -40 Top electrode -45 -40 °C -14.5 °C -50 0.98 6.0 6.5 7.0 7.5 8.0 - C″ PEAK Time /h 0.96 ″ Polynomial coefficient from 𝐷 𝑄𝐹𝐵𝐿 − temperature calibration 0.94 𝑏 𝑐 𝑑 y = -0.0001x 2 - 0.0052x + 0.919 R² = 0.9985 9.19 x 10 -1 0.92 -1.00 x 10 -4 -5.20 x 10 -3 -45 -40 -35 -30 -25 -20 -15 -10 Temperature / o C 19
″ Compensation of 𝐷 𝑄𝐹𝐵𝐿 Objective during primary drying IV 20
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