Detection and characterisation of previously unreported molecular
mobility of pharmaceutically important molecules by Thermally
Stimulated Current (TSC) Spectroscopy
Milan D. Antonijević
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20/08/2014
Overview of presentation
Potential drugs
• Introduction to Thermally Stimulated Current
Spectroscopy (TSC)
• Examples
– amorphous,
– polymorphs,
– co-crystals
• Conclusions
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Potential drugs
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TSC is a general term applied to the measurement of current
generated by temperature-activated relaxation of molecular
dipoles in response to the application of a static electric field
• 1936, Frei and Grotzinger
•
•
•
•
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electrets, ionic crystals
waxes, resins
ceramics, plastic
small organic molecules
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Introduction to TSC
Potential drugs
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Introduction to TSC
Potential drugs
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Introduction to TSC
• SDC (spontaneous depolarisation current)
heating/cooling without an electrical field
• TSPC (thermally stimulated polarisation current)
heating/cooling utilising an applied static electrical field
throughout
• TSDC (thermally stimulated depolarisation current)
after the sample has been subjected to polarisation via a
static electrical field
• TW (thermal windowing) uses a series of discrete
temperature polarisation windows to experimentally
deconvolute the global relaxation process into
elementary relaxation spectra
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TSC Theory
J (T ) =
P(TP )
τ0
 1 T

E
E
'
exp(− ) exp −
exp(− ' )dT 
∫
kT
q
τ
kT


0 T0
τ (T ) = P(T ) / J (T )
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τ (T ) = P(T ) / J (T )
Arrhenius equation
 Ea i
τ i (T ) = τ oi exp
 kT
Eyring equation



h
 ∆Gi  h
 ∆H i 
 ∆S i 
τ i (T ) =
exp
exp −
=
 exp

kT
 kT  kT
 k 
 kT 
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Pharmaceutical Applications
Potential drugs
• Amorphous materials
• Polymorphs
• Batch-to-batch control
• Co-crystals
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TW outputs
Global glass
relaxation process
Different relaxation
modes contributing
to overall process
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Defining Ea - (TW)
Tp(°C) Tmax(°C)
12
35
14
37
16
38
18
39
20
41
22
42
24
43
26
43
28
44
30
45
32
45
34
46
36
46
38
47
40
48
42
50
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𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭 𝑰𝑰𝑰𝑰𝑰𝑰𝑰𝑰𝑰𝑰 (𝒎𝒎) =
Ea
(kJ/mol)
90
93
104
112
126
135
145
157
171
190
208
225
246
259
273
298
ΔH‡
(kJ/mol)
87
90
101
109
123
132
142
154
169
188
205
222
244
257
270
295
𝟏𝟏
𝑬𝑬𝒂𝒂 (𝑻𝑻𝑻𝑻)
𝟏𝟏
𝟐𝟐. 𝟑𝟑𝟑𝟑𝟑𝟑
𝑹𝑹𝑹𝑹𝒈𝒈
20/08/2014
Fragility - Indometacin
Integration
Tmax (K)
Ea (kJmol-1)
m
314.4 (0.1)
314.4 (0.1)
314.4 (0.1)
314.3 (0.1)
314.3 (0.1)
314.3 (0.1)
314.5 (0.1)
314.5 (0.1)
314.5 (0.1)
138.8 (1.0)
178.3 (1.8)
232.3 (1.0)
139.8 (1.5)
180.2 (1.2)
244.4 (2.3)
141.2 (1.5)
183.6 (2.5)
251.5 (1.4)
23.1 (1.0)
29.6 (1.9)
38.6 (1.0)
23.2 (1.5)
30.0 (1.2)
40.6 (2.3)
23.4 (1.5)
30.5 (2.0)
41.8 (1.4)
window (K)
TSDC (Tp = 303 K)
TSDC (Tp = 313 K)
TSDC (Tp = 323 K)
20
10
5
20
10
5
20
10
5
1  E a (Tg ) 
m=


2.303  RTg 
Integration window 2 K
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Tm (K)
Ea (kJmol-1)
τ (s)
m
TSDC (Tp = 303 K)
314.4 (0.1)
376.0 (3.3)
59.3 (9.0)
62.4 (3.3)
TSDC (Tp = 313 K)
314.3 (0.1)
388.3 (4.0)
54.8 (8.0)
64.5 (4.0)
TSDC (Tp = 323 K)
314.5 (0.1)
385.8 (3.2)
51.4 (7.4)
64.1 (3.2)
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Pharmaceutical Applications
Potential drugs
• Amorphous materials
• Polymorphs
• Batch-to-batch control
• Co-crystals
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Caffeine
Exists in two polymorphic forms:
Form I, unstable at room T, Trigonal
Form II, stable at room T, Monoclinic
Transition point: 141 ± 2°C
Melting Point: 236 - 243°C (British Pharmacopoeia)
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Caffeine - TSDC Results
Form I
α-process 139ºC
γ-process -8ºC
β1-process 91ºC
β2-process 107ºC
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Form II
Form II only - polymorphic transition
Forms I and II - orientation of side group
Form II
Form I - orientation/mobility of sub-unit
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Caffeine - SDC Results
Form I - negative peak at -8oC and 112oC
Form II - negative peak at 52oC
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Kinetic Parameters - TSC Method
TSDC
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SDC
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Sensitivity
12
10
Current (10-13A)
8
6
4
2
3.0
2.5
Total Charge (C)
500V
400V
300V
200V
100V
2.0
1.5
1.0
0
0.5
180
200
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220
240
260
Temperature (K)
280
300
320
50
100
150
200
250
300
350
400
450
500
550
Electrical Field (V/mm)
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Pharmaceutical Applications
Potential drugs
• Amorphous materials
• Polymorphs
• Batch-to-batch control
• Co-crystals
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2.00E-013
2.00E-013
1.50E-013
1.50E-013
1.00E-013
1.00E-013
Current (A)
Current (A)
Batch to Batch variations
5.00E-014
5.00E-014
0.00E+000
0.00E+000
-5.00E-014
-5.00E-014
-1.00E-013
-100 -80 -60 -40 -20
0
20
40
60
0
Temperature ( C)
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80 100 120 140 160
-1.00E-013
-100 -80 -60 -40 -20
0
20
40
60
80 100 120 140 160
0
Temperature( C)
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Batch to Batch variations
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Pharmaceutical Applications
Potential drugs
• Amorphous materials
• Polymorphs
• Batch-to-batch control
• Co-crystals
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SA/BA co-crystal system
• 1:1 molar ratio co-crystal (CC) of salicylic acid (SA) and benzamide (BA)
• 1:1 molar ratio physical mixture (PM)
Potential drugs
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Primary transitions:
BA = 128oC
SA = 159oC
CC = 119oC
PM = 110oC
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SA/BA co-crystal system
Potential drugs
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SA/BA co-crystal system
Potential drugs
Tc:
CC-A = 125oC
CC-B = 119oC
PM= 110oC
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Conclusions
Detection and characterisation of amorphous
materials
Characterisation (Kinetics) of polymorphic
transitions and co-crystal systems
Detection of beta and gama relaxation processes
Links between secondary (beta and gama) and
primary relaxation
Batch to batch variations
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Acknowledgments
PhD students:
Samuel Owusu-Ware
Anthony Cherry
Colleagues:
Prof. Babur Chowdhry
Prof. Stephen Leharne
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Thank you for
listening
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