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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

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SLIDE 1

Through-Vial Impedance Spectroscopy (TVIS)

A novel process analytical technology for the development of pharmaceutical products and processes

  • PROF. GEOFF SMITH

Professor of Pharmaceutical Process Analytical Technology Leicester School of Pharmacy De Montfort University, Leicester, UK

Vienna, Austria May 24 24 – 25 25, , 2018 www.dmu.ac.uk/tvis

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SLIDE 2

2

Through Vial Impedance Spectroscopy

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 (π‘ˆπ‘—, π‘ˆπ‘)
  • Drying rate determination
  • Heat transfer coefficient (𝐿𝑀) determination
  • Acknowledgements
  • TVIS dielectric loss mechanisms
slide-3
SLIDE 3

3

Through Vial Impedance Spectroscopy

Through Vial Impedance Spectroscopy (TVIS) Description of Measurement System

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SLIDE 4

4

Through Vial Impedance Spectroscopy

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 β€œThrough Vial Impedance Spectroscopy”
  • Features
  • Single vial β€œnon-product invasive”
  • Both freezing and drying characterised in a single technique
  • Non-perturbing to the packing of vials
  • Stopper mechanism unaffected
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SLIDE 5

5

Through Vial Impedance Spectroscopy

Freeze drying chamber Stimulating voltage Resultant current LyoDEATM measurement software Junction box TVIS system (I to V convertor) Pass-through TVIS measurement vial LyoViewTM analysis software

slide-6
SLIDE 6

6

Through Vial Impedance Spectroscopy

Through Vial Impedance Spectroscopy (TVIS) Applications

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SLIDE 7

7

Through Vial Impedance Spectroscopy

Through Vial Impedance Spectroscopy (TVIS)

0.0 0.2 0.4 0.6 0.8 1 2 3 4 5 6

  • Cβ€³/ pF

Log Frequency

FPEAK FPEAK Liquid State Solid State

0.0 0.1 0.2 0.3 0.4 0.5 0.6

1 2 3 4 5 6

  • Cβ€³ / pF

Log Frequency

Cβ€³PEAK

increase

Drying time

0.0 0.2 0.4 0.6 0.8 1 2 3 4 5 6

  • Cβ€³ /pF

Log Frequency

  • 38 oC
  • 18 oC

Monitoring Phase Behaviour (ice nucleation temperature and solidification end points by using 𝐺

𝑄𝐹𝐡𝐿

𝐺

𝑄𝐹𝐡𝐿 temperature calibration

for predicting temperature of the product in primary drying Surrogate drying rate (from

𝑒𝐷𝑄𝐹𝐡𝐿

β€³

𝑒𝑒

) 𝐷′(~ 100 kHz) is highly sensitive to low ice volumes; therefore it could be used for determination end point of primary drying

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SLIDE 8

8

Through Vial Impedance Spectroscopy

Imaginary Part of Capacitance Real Part of Capacitance High frequency

Liquid state Liquid state Frozen solid Frozen solid

low frequency Annealing = Re-heating and Re-cooling

Re-heating Re-heating

Intermediate frequency

Re-cooling Re-cooling

low frequency

Primary drying Primary drying

low frequency

TVIS Response Surface (3D-Plot)

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SLIDE 9

9

Through Vial Impedance Spectroscopy

  • Data analysing software (LyoView β„’)

identifies the peak frequency (𝐺𝑄𝐹𝐡𝐿 ) and peak amplitude (𝐷𝑄𝐹𝐡𝐿

β€³

) in the imaginary part of the capacitance spectrum

Dielectric loss spectrum

0.00 0.10 0.20 0.30 0.40 1 2 3 4 5 6

  • Cβ€³/pF

Log Frequency

𝐺𝑄𝐹𝐡𝐿 𝐷𝑄𝐹𝐡𝐿

β€³

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SLIDE 10

10

Through Vial Impedance Spectroscopy

Through Vial Impedance Spectroscopy (TVIS) Dual-electrode system and its applications (Ice temperature, Drying rate and Heat transfer coefficient )

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SLIDE 11

11

Through Vial Impedance Spectroscopy

Dual-electrode system

Electrode height ~10 mm Electrode distance from base ~3 mm

Standard TVIS vial (Single electrode system)

Electrode Dimension 10 x 19 mm

New feature of TVIS vial (Dual electrode system)

Electrode Dimension Top electrode (TE): 10 x 19 mm Bottom Electrode (BE): 5 x 19 mm Bottom electrode height ~10 mm Electrode distance from base ~3 mm Top electrode height ~15 mm Gap between electrode ~3 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 𝐿𝑀 determination.

~3.4 g of water (βˆ… = 𝟏. πŸ–) ~8 g of water (βˆ… = 𝟏. πŸ–)

slide-12
SLIDE 12

12

Through Vial Impedance Spectroscopy

  • π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ : TVIS predicted temperature

from top electrode (TE)

  • π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹 : TVIS predicted temperature

from bottom electrode (BE)

Temperature Determination

π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹 Both π‘ˆπ‘— and π‘ˆπ‘ can be estimated by extrapolating from the temperatures predicted from the centers of top electrode (π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ) and bottom electrode (π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹). Dual electrode

3 mm gap 3 mm gap 5 x 19 mm 15 x 19 mm π‘ˆπ‘ π‘ˆπ‘—

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SLIDE 13

13

Aims & Objectives

Aims

To determine the heat transfer coefficient (𝐿𝑀) by using a novel dual electrode TVIS approach

Temperature calibration of log 𝐺

𝑄𝐹𝐡𝐿 of top electrode (π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ) and

bottom electrode (π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹)

I

Prediction ice temperatures for both electrodes during primary drying

II

Temperature calibration of 𝐷𝑄𝐹𝐡𝐿

β€³

III

Compensation of 𝐷𝑄𝐹𝐡𝐿

β€³

during primary drying

IV

Calibration of 𝐷𝑄𝐹𝐡𝐿

β€³

for ice layer height

V

Estimation of ice layer height during primary drying

VI

Prediction ice temperatures at (i) sublimation interface (π‘ˆ

𝑗) and (ii)

vial’s base (π‘ˆ

𝑐) including qualification TVIS technique (π‘ˆ 𝑗 = π‘ˆ 𝑄𝑗=𝑄𝑑 )

VII

Comparison of TVIS drying rate (βˆ†π‘› βˆ†π‘’ ) with gravimetric method (weight loss)

VIII

Determination (i) the drying rate ( βˆ†π‘› βˆ†π‘’ ) and (ii) ice base temperature (π‘ˆπ‘) during the steady state period

IX

Heat transfer coefficient (𝐿𝑀) calculation

X

slide-14
SLIDE 14

14

Objective

Temperature calibration of log 𝐺

𝑄𝐹𝐡𝐿 of top electrode

(π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ) and bottom electrode (π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹)

I

Annealing the sample In-line TVIS measurement Identifying peak frequency (𝐺

𝑄𝐹𝐡𝐿)

using LyoView β„’ software Calibration plot (temperature vs Log 𝐺

𝑄𝐹𝐡𝐿)

Predicting product temperature using calibration plot

slide-15
SLIDE 15

15

  • 50
  • 45
  • 40
  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

6.0 6.5 7.0 7.5 8.0

Temperature / oC Time /h

Objective

Shelf Temp. 𝑼 𝑼𝑫 𝟐 𝑼 𝑼𝑫 πŸ‘ 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1 2 3 4 5 6

  • Cβ€³ / pF

Log Frequency

  • 41.5 Β°C
  • 25 Β°C

y = -1.0225x2 + 30.106x - 114.74 RΒ² = 0.9999 y = -0.543x2 + 26.718x - 108.5 RΒ² = 0.9999

  • 50
  • 45
  • 40
  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8

Temperature /oC Log FPEAK

Bottom electrode Top electrode Top electrode

𝑏 𝑐 𝑑

TE

  • 1.02

30.1

  • 114

BE

  • 5.43 x 10-1

26.7

  • 109

Polynomial coefficient from 𝑀𝑝𝑕 𝐺

𝑄𝐹𝐡𝐿 βˆ’ temperature calibration

Temperature calibration of log 𝐺

𝑄𝐹𝐡𝐿 of top electrode

(π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ) and bottom electrode (π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹)

I

slide-16
SLIDE 16

16

Objective

Prediction ice temperatures for both electrodes during primary drying

II

slide-17
SLIDE 17

17

Objective

  • 45
  • 40
  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

5 1 2 3 4 5

Temperature /oC Time / h

π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹 π‘ˆ π‘ˆπ· 2 π‘ˆ π‘ˆπ· 1 Shelf Temperature (π‘ˆ

𝑑)

  • 38
  • 36
  • 34
  • 32
  • 30
  • 28

1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8

Temperature /oC Time / h

π‘ˆ π‘ˆπ· 2 π‘ˆ π‘ˆπ· 1 π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹 π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ

  • Temp. constant
  • Temp. constant

π‘ˆ(𝑄𝑗=𝑄𝐷@270πœˆπ‘π‘π‘ ) = βˆ’33.2 ℃

Prediction ice temperatures for both electrodes during primary drying

II

The product temperature predicted by TVIS can demonstrate the temperature gradient across ice cylinder height

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SLIDE 18

18

Objective

Temperature calibration of 𝐷𝑄𝐹𝐡𝐿

β€³

III

Annealing the sample In-line TVIS measurement Identifying peak amplitude (𝐷𝑄𝐹𝐡𝐿

β€³

) using LyoView β„’ software Calibration plot (𝐷𝑄𝐹𝐡𝐿

β€³

vs temperature) Temperature compensation of 𝐷𝑄𝐹𝐡𝐿

β€³

using calibration plot

slide-19
SLIDE 19

19

  • 50
  • 45
  • 40
  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

6.0 6.5 7.0 7.5 8.0

Temperature / oC Time /h

Objective

Shelf Temp. 𝑼 𝑼𝑫 𝟐 𝑼 𝑼𝑫 πŸ‘ 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1 2 3 4 5 6

  • Cβ€³ / pF

Log Frequency

  • 41.5 Β°C
  • 25.5 Β°C

Top electrode

y = -0.0001x2 - 0.0052x + 0.919 RΒ² = 0.9985

0.92 0.94 0.96 0.98 1.00

  • 45 -40 -35 -30 -25 -20 -15 -10
  • Cβ€³PEAK

Temperature /oC

𝑏 𝑐 𝑑

  • 1.00 x 10-4
  • 5.20 x 10-3

9.19 x 10-1 Polynomial coefficient from 𝐷𝑄𝐹𝐡𝐿

β€³

βˆ’ temperature calibration

  • 14.5 Β°C
  • 40 Β°C

Top electrode

Temperature calibration of 𝐷𝑄𝐹𝐡𝐿

β€³

III

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SLIDE 20

20

Objective

Compensation of 𝐷𝑄𝐹𝐡𝐿

β€³

during primary drying

IV

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SLIDE 21

21 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1 2 3 4 5

  • Cβ€³PEAK / pF

Time / h

Cβ€³peak Δˆβ€³peak Ĉ_(𝑄𝐹𝐡𝐿(4.9 β„Ž))^β€³ 0.578 π‘žπΊ

Objective

  • During primary drying, 𝐷𝑄𝐹𝐡𝐿

β€³

is attributed to both the loss of ice and product temperature; therefore, it requires a standardization factor (βˆ…) for temperature compensation:

  • The expression for βˆ…(π‘ˆ) can be re-written in terms of

the polynomial coefficients (slide 22):

  • Values of 𝐷𝑄𝐹𝐡𝐿

β€³

during primary drying are then standardized to the reference temperature by dividing by βˆ…(π‘ˆ) to give a standardized peak amplitude of Δˆπ‘Έπ‘­π‘©π‘³

β€³ βˆ…(π‘ˆ) = 𝐷𝑄𝐹𝐡𝐿

β€³

(π‘ˆ) 𝐷𝑄𝐹𝐡𝐿

β€³

(π‘ˆ

𝑠𝑓𝑔)

𝐷𝑄𝐹𝐡𝐿

β€³

(π‘ˆ) and 𝐷𝑄𝐹𝐡𝐿

β€³

(π‘ˆπ‘ π‘“π‘”) are the peak amplitudes at temperatures (π‘ˆ) and reference temperature (π‘ˆπ‘ π‘“π‘”) during the re-heating ramp. In this presentation, a temperature of -20 Β°C is used as the reference temperature value βˆ…(π‘ˆ) =

π‘π‘ˆ2+π‘π‘ˆ+𝑑 π‘π‘ˆπ‘ π‘“π‘”2+π‘π‘ˆπ‘ π‘“π‘”+𝑑

Δˆπ‘„πΉπ΅πΏ(0 β„Ž)

β€³

0.971 π‘žπΊ 𝐷𝑄𝐹𝐡𝐿(0)

β€³

0.931 π‘žπΊ 𝐷𝑄𝐹𝐡𝐿(4.9 β„Ž)

β€³

0.571 π‘žπΊ

The standardized 𝐷𝑄𝐹𝐡𝐿

β€³

is defined as Δˆπ‘Έπ‘­π‘©π‘³

β€³

  • 45
  • 40
  • 35
  • 30

1 2 3 4 5

Temperature /oC Time / h

π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ

Compensation of 𝐷𝑄𝐹𝐡𝐿

β€³

during primary drying

IV

Δˆπ‘Έπ‘­π‘©π‘³

β€³

= 𝐷𝑄𝐹𝐡𝐿

β€³

(π‘ˆ) βˆ…(π‘ˆ)

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SLIDE 22

22

Objective

Calibration of 𝐷𝑄𝐹𝐡𝐿

β€³

for ice layer height

V

Filling water into TVIS vial Freezing the sample In-line TVIS measurement Thawing the sample Identifying 𝐷𝑄𝐹𝐡𝐿

β€³

using simple peak finding Calibration plot (𝐷𝑄𝐹𝐡𝐿

β€³

vs temperature)

slide-23
SLIDE 23

23

Objective

Calibration of 𝐷𝑄𝐹𝐡𝐿

β€³

for ice layer height

V

0.0 0.5 1.0 1.5 2.0 1 2 3 4 5 6

  • Cβ€³ (Imag. part / pF)

Log Frequency

2 4 6 8 10 12 14 16 0.0 0.5 1.0 1.5

Ice height from bottom edge of electrode / mm

  • Cβ€³PEAK / pF

0 mm 15 mm

slide-24
SLIDE 24

24

Objective

Estimation of ice layer height during primary drying

VI

slide-25
SLIDE 25

25

Objective

At 2.4 h into primary drying Δˆπ‘„πΉπ΅πΏ

β€³

= 0.863 pF Ice height = 9.7485 x 0.863 + 1.0462 = 9.459 mm (from the bottom edge of TE) Ice front height = 9.459+(2+5+3) = 19.46 mm

Bottom electrode (BE) 5 x 19 mm

3 mm gap

Freeze Dryer Shelf

y = 9.7485x + 1.0462

2 4 6 8 10 12 14 16 0.0 0.5 1.0 1.5

Ice height from bottom edge of electrode / mm

  • Cβ€³PEAK / pF

3 mm gap

Top electrode (TE) 15 X 19 mm

𝐽𝑑𝑓 β„Žπ‘“π‘—π‘•β„Žπ‘’(β„Ž) = 9.7485 Γ— 𝐷𝑄𝐹𝐡𝐿

β€³

+ 1.0462

At -20 Β°C

Freeze drying shelf 2 mm 5 mm 3 mm Δˆπ‘„πΉπ΅πΏ

β€³

0.863 pF 19.46 mm 10 mm 9.46 mm

Gradient of the line (π‘›β„Ž/𝑑)

Estimation of ice layer height during primary drying

VI

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SLIDE 26

26

  • Surrogate drying rate can be estimated

in terms of decreasing ice height

  • The dependency of 𝐷𝑄𝐹𝐡𝐿

β€³

  • n the ice

cylinder height in linear region

Objective

16 17 18 19 20 21 1 2 3 4 5

Ice height (β„Ž)/ mm Time / h 𝑧 = 9.7485𝑦 + 1.0462 𝐽𝑑𝑓 β„Žπ‘“π‘—π‘•β„Žπ‘’ β„Ž π‘€π‘—π‘œπ‘“π‘π‘  π‘•π‘ π‘π‘’π‘—π‘“π‘œπ‘’ (π‘›β„Ž/𝑑) 𝐷𝑄𝐹𝐡𝐿

β€³

β„Ž(0 β„Ž) 20.50 mm β„Ž(4.9 β„Ž) 16.68 mm

Estimation of ice layer height during primary drying

VI

slide-27
SLIDE 27

27

Objective

Prediction ice temperatures at (i) sublimation interface (π‘ˆπ‘—) and (ii) vial’s base (π‘ˆπ‘) including qualification TVIS technique (π‘ˆπ‘— = π‘ˆ 𝑄𝑗=𝑄𝑑 )

VII

slide-28
SLIDE 28

28

Prediction ice temperatures at (i) sublimation interface (π‘ˆπ‘—) and (ii) vial’s base (π‘ˆπ‘) including qualification TVIS technique (π‘ˆπ‘— = π‘ˆ 𝑄𝑗=𝑄𝑑 )

VII

Freeze drying shelf

Objective

5 10 15 20 25

  • 34
  • 33
  • 32
  • 31
  • 30
  • 29

Ice height (β„Ž) / mm Temperature (π‘ˆ) / oC

  • 38
  • 36
  • 34
  • 32
  • 30
  • 28

1.2 1.6 2.0 2.4 2.8

Temperature /oC Time / h

4.5 mm π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ

  • 32.3 ˚C

14.73 mm

18 19 20 21 1.2 1.6 2.0 2.4 2.8

Ice height (β„Ž)/ mm Time / h

Ice height 19.46 mm at 2.4 h

π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹

  • 30.6 ˚C

At 2.4 h Ice height for π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ = 2 + 5 + 3 +(

9.46 2 ) = 14.73 mm

Ice height for π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹 = 2 +(

5 2)

= 4.50 mm

2 mm 5 mm 3 mm 9.46 mm

β„Ž = βˆ’5.93 Γ— π‘ˆ βˆ’ 176.79

β„Ž = βˆ’5.93 Γ— π‘ˆ βˆ’ 176.79 π‘ˆ = β„Ž + 176.79 βˆ’5.93

𝑼𝒋 -33.1 ˚C 𝑼𝒄 -29.8 ˚C

0 mm 19.46 mm π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹 π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ π‘ˆπ‘— π‘ˆπ‘

  • 30.6 ˚C
  • 32.3 ˚C

Ice Temperature At interface (π‘ˆπ‘—, 19.46 mm) =

β„Ž+176.79 βˆ’5.93

=

19.46+176.79 βˆ’5.93

= -33.1 ˚C At vial’s base (π‘ˆπ‘, 0 mm) =

β„Ž+176.79 βˆ’5.93

=

0+176.79 βˆ’5.93 = -29.8 ˚C

slide-29
SLIDE 29

29

Objective

The product temperature at ice interface predicted by using a 2-points temperature extrapolation close to the temperature of ice vapour at chamber pressure of 270 Β΅bar (π‘ˆ(𝑄𝑗=𝑄𝐷@270πœˆπ‘π‘π‘ ))

  • 45
  • 40
  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

5 1 2 3 4 5

Temperature /oC Time / h

π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹 π‘ˆ π‘ˆπ· 2 π‘ˆπ‘— π‘ˆπ‘ π‘ˆ π‘ˆπ· 1 Shelf Temperature (π‘ˆ

𝑑)

  • 38
  • 36
  • 34
  • 32
  • 30
  • 28

1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8

Temperature /oC Time / h

π‘ˆ π‘ˆπ· 2 π‘ˆπ‘ π‘ˆ π‘ˆπ· 1 π‘ˆ 𝐺𝑄𝐹𝐡𝐿 𝐢𝐹 π‘ˆ 𝐺𝑄𝐹𝐡𝐿 π‘ˆπΉ π‘ˆπ‘—

  • Temp. constant

(π‘ˆπ‘—= -33.1Β± 0.05˚C )

  • Temp. constant

(π‘ˆπ‘—= -33.1Β± 0.05˚C )

π‘ˆ(𝑄𝑗=𝑄𝐷@270πœˆπ‘π‘π‘ ) = βˆ’33.2 ℃

Prediction ice temperatures at (i) sublimation interface (π‘ˆπ‘—) and (ii) vial’s base (π‘ˆπ‘) including qualification TVIS technique (π‘ˆπ‘— = π‘ˆ 𝑄𝑗=𝑄𝑑 )

VII

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Objective

Comparison of TVIS drying rate ( βˆ†π‘› βˆ†π‘’ ) with gravimetric method (weight loss)

VIII

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Objective

  • Drying rate is based on the assumption of a planar sublimation front
  • The change in ice cylinder height (β„Ž) can be equated to the change in ice

volume (v)

Where 𝑠 is internal radius of vial and 𝐡 is internal cross section area of vial (= πœŒπ‘ 2)

  • Ice volume can be converted to ice mass (𝑛) by multiplying with ice density (πœπ‘—)
  • Hence; drying rate (

βˆ†π‘› βˆ†π‘’ ) can be expressed by

v π‘‘π‘§π‘šπ‘—π‘œπ‘’π‘“π‘  = πœŒπ‘ 2β„Ž = π΅β„Ž 𝑛 = πœπ‘— βˆ™ πœŒπ‘ 2β„Ž = πœπ‘— βˆ™ π΅β„Ž 𝑬𝒔𝒛𝒋𝒐𝒉 𝒔𝒃𝒖𝒇 (βˆ†π’ βˆ†π’– ) = 𝝇𝒋 βˆ™ 𝑩 βˆ™ π’Š π’–πŸ βˆ’ π’Š(π’–πŸ‘) π’–πŸ‘ βˆ’ π’–πŸ

Comparison of TVIS drying rate ( βˆ†π‘› βˆ†π‘’ ) with gravimetric method (weight loss)

VIII

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Objective

  • An average surrogate drying rate calculation

Ice density (πœπ‘— )at -32 ˚C = 0.920 gοƒ—cm-3 Internal vial diameter (VC010-20C) = 2.21 cm Cross-section area (𝐡) = 3.80 cm2 Ice height at 0 h (β„Ž(0 β„Ž)) = 20.50 mm Ice height at 4.9 h (β„Ž(4.9 β„Ž)) = 16.68 mm πΈπ‘ π‘§π‘—π‘œπ‘• 𝑠𝑏𝑒𝑓 = 0.920 𝑕 βˆ™ π‘‘π‘›βˆ’3 Γ— 3.80 𝑑𝑛2 Γ— 20.50 βˆ’ 16.68 Γ— 10βˆ’1𝑑𝑛 4.9 βˆ’ 0 β„Ž = 𝟏. πŸ‘πŸ– 𝒉 βˆ™ π’Šβˆ’πŸ

Drying rate

π‘ˆπ‘Šπ½π‘‡ 0.27 g/h 𝐻𝑠𝑏𝑀𝑗𝑛e𝑒𝑠𝑗𝑑 0.25 g/h

πΈπ‘ π‘§π‘—π‘œπ‘• 𝑠𝑏𝑒𝑓 (βˆ†π‘› βˆ†π‘’ ) = πœπ‘— βˆ™ 𝐡 βˆ™ β„Ž(𝑒1) βˆ’ β„Ž(𝑒2) 𝑒2 βˆ’ 𝑒1

16 17 18 19 20 21 1 2 3 4 5

Ice height (β„Ž)/ mm Time / h β„Ž(0 β„Ž) 20.50 mm β„Ž(4.9 β„Ž) 16.68 mm

Comparison of TVIS drying rate ( βˆ†π‘› βˆ†π‘’ ) with gravimetric method (weight loss)

VIII

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Objective

Determination (i) the drying rate (βˆ†π‘› βˆ†π‘’ ) and (ii) ice base temperature (π‘ˆπ‘) during the steady state period

IX

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  • 28

1 2 3 4 5

Temperature /oC Time / h

16 17 18 19 20 21 1 2 3 4 5

Ice height (β„Ž)/ mm Time / h

π‘ˆπ‘— π‘ˆπ‘

  • Temp. constant

π‘ˆπ‘—= -33.1Β± 0.05˚C π‘ˆπ‘= -29.8Β± 0.03˚C

β„Ž(2 β„Ž) 19.94 mm β„Ž(2.8 β„Ž) 18.98 mm

  • Drying rate during the steady state

Ice density (πœπ‘— ) at -32˚C = 0.920 gοƒ—cm-3

(Calculated ice temperature between π‘ˆπ‘— & π‘ˆπ‘)

Internal vial diameter (VC010-20C) = 2.21 cm Cross-section area (𝐡) = 3.80 cm2 Ice height at 2 h (β„Ž(2 β„Ž)) = 19.94 mm Ice height at 2.8 h (β„Ž(2.8 β„Ž)) = 18.98 mm πΈπ‘ π‘§π‘—π‘œπ‘• 𝑠𝑏𝑒𝑓 (βˆ†π‘› βˆ†π‘’ ) = πœπ‘— βˆ™ 𝐡 βˆ™ β„Ž(𝑒1) βˆ’ β„Ž(𝑒2) 𝑒2 βˆ’ 𝑒1

πΈπ‘ π‘§π‘—π‘œπ‘• 𝑠𝑏𝑒𝑓 = 0.920 𝑕 βˆ™ π‘‘π‘›βˆ’3 Γ— 3.80 𝑑𝑛2 Γ— 19.94 βˆ’ 18.98 Γ— 10βˆ’1𝑑𝑛 2.8 βˆ’ 2.0 β„Ž

= 𝟏. πŸ“πŸ‘ 𝒉 βˆ™ π’Šβˆ’πŸ

π‘ˆπ‘π‘€π‘• ~32 ˚C

TVIS parameters used for determination:

βˆ†π‘› βˆ†π‘’ = 0.42 gΒ·h-1

π‘ˆπ‘= -29.8˚C

Objective

Determination (i) the drying rate (βˆ†π‘› βˆ†π‘’ ) and (ii) ice base temperature (π‘ˆπ‘) during the steady state period for heat transfer coefficient (𝐿𝑀) calculation

IX

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Objective

Heat transfer coefficient (𝐿𝑀) calculation

X

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Parameters TVIS Drying rate at steady state (g/h) (2-2.8 h into primary drying) 0.42 Shelf Temperature, π‘ˆ

𝑑 (K)

273.3 Vial’s base Temperature, π‘ˆπ‘(K) 243.3

Objective

Heat transfer coefficient (𝐿𝑀) calculation

X

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0.0E+0 1.0E-4 2.0E-4 3.0E-4 4.0E-4 5.0E-4 6.0E-4 7.0E-4 8.0E-4 100 200 300 400

Over all heat transfer Coefficient (cals-1cm-2K-1) Pressure (mTorr)

TVIS Tchessalov S (2017)

𝐿𝑀(TVIS @ 270 bar) 5.73 x 10-4

𝑀 is the latent heat of sublimation of ice (2844 Jοƒ—g-1 or 679.7 cal οƒ—g-1) and 𝐡𝑓 is external cross-sectional area of the base of the TVIS vial (4.62 cm2)

𝐿𝑀 = 𝑀 βˆ†π‘› βˆ†π‘’ 𝐡𝑓(π‘ˆ

𝑑 βˆ’ π‘ˆπ‘)

𝐿𝑀(270 𝑐𝑏𝑠) = 𝑀 βˆ†π‘› βˆ†π‘’ 𝐡𝑓(π‘ˆ

𝑑 βˆ’ π‘ˆπ‘)

= 679.7 π‘‘π‘π‘š βˆ™ π‘•βˆ’1 Γ— 0.42 𝑕 βˆ™ β„Žβˆ’1 4.62 𝑑𝑛2 Γ— 273.3 βˆ’ 243.3 𝐿 = 2.06 π‘‘π‘π‘š βˆ™ β„Žβˆ’1 βˆ™ π‘‘π‘›βˆ’2 βˆ™ πΏβˆ’1 = 5.73 Γ— 10βˆ’4π‘‘π‘π‘š βˆ™ π‘‘βˆ’1 βˆ™ π‘‘π‘›βˆ’2 βˆ™ πΏβˆ’1 𝐿𝑀(270 πœˆπ‘π‘π‘ ) = 5.73 Γ— 10βˆ’4π‘‘π‘π‘š βˆ™ π‘‘βˆ’1 βˆ™ π‘‘π‘›βˆ’2 βˆ™ πΏβˆ’1

𝑀 βˆ†π‘› βˆ†π‘’ = 𝐡𝑓𝐿𝑀(π‘ˆ

𝑑 βˆ’ π‘ˆπ‘)

Parameters TVIS Drying rate at steady state (g/h) (2-2.8 h into primary drying) 0.42 Shelf Temperature, π‘ˆ

𝑑 (K)

273.3 Vial’s base Temperature, π‘ˆπ‘(K) 243.3

Objective

Heat transfer coefficient (𝐿𝑀) calculation

X

Pikal, et al. (1984)

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Additional comments

Qualification of steady state heat transfer mechanisms

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A single vial technique

Pikal, et al. (1984)

The mean sublimation rate was calculated from the mass

  • f ice sublimed and the time required for sublimation.
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Assumption for π‘³π’˜ determination

  • How do we know that the heat transfer mechanisms are constant up to 25%

loss of ice mass?

  • If the heat transfer mechanisms change because of ice- glass interface contact
  • r because of the change of ice shape (surface area) then surely heat transfer

coefficient will change?

  • It requires a technique to qualify when the heat transfer mechanisms change
  • So can TVIS demonstrate when ice leaves the glass wall interface?
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  • 44
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  • 32
  • 28

1 2 3 4 5

Temperature /oC Time / h

16 17 18 19 20 21 1 2 3 4 5

Ice height (β„Ž)/ mm Time / h

π‘ˆπ‘— π‘ˆπ‘

  • Temp. constant

π‘ˆπ‘—= -33.1Β± 0.05˚C π‘ˆπ‘= -29.8Β± 0.03˚C π‘ˆπ‘π‘€π‘• ~32 ˚C

I II

Limitation of TVIS System ?

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Discussion

  • Decrease in 𝐺𝑄𝐹𝐡𝐿 suggests that the temperature may be decreasing after the

steady state period, contrary to accepted knowledge that the temperature starts to increase owing to a reduction in drying rate and hence the degree of self cooling

  • Decrease in 𝐺𝑄𝐹𝐡𝐿 is more likely to be due to a change in the ice-glass contact

associated with a change in the shape of the ice cylinder.

Conclusion

  • The period for determining the drying rate should be decreased from 25% ice

loss to 10% for TVIS to give reliable estimates for Kv

  • Opportunity to cycle through shelf temperature and chamber pressure to

create the design space for Kv determinations as a function of shelf position.

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Limitations

  • 𝐷𝑄𝐹𝐡𝐿

β€³

and 𝐺𝑄𝐹𝐡𝐿parameters rely on intimate contact of ice cylinder with glass wall

  • Cable length limited to 1m at present
  • C-TVIS not compatible with front loading system
  • Incompatible with TCs in same TVIS vial (use fibre optic sensors – INFAP)
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Future Work

  • Development dryer mapping of sublimation

characteristics

  • heat transfer coefficients (πΏπ‘Š)
  • dry layer resistance (𝑆𝑄)
  • Instrument Development
  • Contact C-TVIS instrument (2018)
  • Non-contact TVIS (2018-19)
  • Micro-well screening
  • Vial clusters in batch FD
  • TVIS - Shuttle (2019-20)
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  • De Montfort University, School of Pharmacy
  • Evgeny Polygalov: co-inventor of TVIS instrument
  • Yowwares Jeeraruangrattana. PhD student
  • Bhaskar Pandya. PhD student
  • Irina Ermolina. Senior Lecturer

Acknowledgements, Recent Projects & Collaborators

Biopharmaceutical Stability at Room Temperature Analytical Technologies for the Stabilization of Biopharmaceuticals Government Support for industry

LyoDEA

Lyophilization process analytics By dielectric analysis

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Thank you