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Thermal Analisys Pharmaceuticals
Thermal Analisys Pharmaceuticals
Thermal Analisys Pharmaceuticals
techniques in pharmaceutical
industry
D. Giron, Chemical and Analytical Development,
Novartis Pharma Basel
Content
Introduction
Single compounds, example salt forms
Characterization of Solid state and examples of combined
techniques
DSC purity determination
Study of polymeric excipients
Examples of use for Drug products
Determination of freezable water
GMP: examples of standards for calibration of DSC
Quantitation
Example of validation of TG
Sensitivity DSC
Determination of amorphous content
Quantitation in drug products
Polymorphism
Investigation, choice of the salt form, manufacture, control
of crystallization, drying, milling, batch control
Amorphous state
Temperature Tg and influence of moisture, excipients
Quantitation
DSC, microcalorimetry
Purity
Raw materials: purification, stability
DSC
Stability
Thermal decomposition, kinetics, compatibility, stability
Polymers
Characterization, miscibility, control, stability
Drug products
Physical interactions, phase diagrams
DSC
Sub-ambient DSC
Identification, quantitation
DSC, TG
DSC, microcalorimetry
Combined techniques
DSC or microcalorimetry and TG sensitive but not
specific.
Spectroscopic and cristallographic informations
Lack of melting point (decomposition)
Solid transformation may have too small energies
Influence of impurities on melting point
Influence of amorphous on melting enthalpies
Dehydration/Hydration studies in situ, no artefact
Combined DSC/TG, DSC/Hot stage microscopy,
DSC/IR or Raman microscopy, DSC/X-ray
DVS/X-ray, TG/MS, TG/IR, TG/GC
Use of microcalorimetry
Chemical & Analytical Development
TA user meeting D. Giron
Solid State/Definitions
Energy diagrams
Enantiotropy
Monotropy
Oxybuprocaine hydrochloride
Oxybuprocaine HCl has two forms enantiotropically related. The
transformation of the high melting form in the stable form in solid state
is kinetically hindered.
Oxybuprocaine hydrochloride. XRD before and after the endothermic peak B =>A
B ->A 150oC
Form B
Form A
Form B
Form B
Form C
Form D
DSC onset
111 oC
128 oC
118 oC
109 oC
93
981)
92
89
65
<0.5%
2%
needles
Plates/needles
< 0.5%
>2%
108- 112 oC
Temperature
Weight loss by TG
<0.5%
<0.5%
Morphology
needles
needles
TG after 1 day at
92% RH
< 0.5%
< 0.5%
Density g/cm3
1.400
1.422
1.411
Solubility water
0.27
0.17
0.2
20 oC in % (w/w)
Chemical & Analytical Development
TA user meeting D. Giron
0.18
Solvates / Hydrates
Influence of experimental conditions
Melting A
DSC
Ethanol solvate
Solvate -> C
C -> A
Acetone solvate
40C
TG
Ethanol solvate
40C
m = 46
Melting A
Acetone solvate
DSC
125C
125C
Solvate -> C
C ->A
170C
TG
m = 58
170C
Tetracaine. HCl
Relationships between all forms
Degradation
lactam + water
BA
TG-MS
Loss of
water
m = 18
lactam
185 C
150 C
120 C
Degradation in lactam
Chemical & Analytical Development
TA user meeting D. Giron
Identification of polymorphs
Onset T (C)
certificate
-31.3
Standard
Substance
Naphthalene
(80.2C)
H (J/g)
148.6
H2O
0.0
Benzil (94.7C)
112.0
4-Nitrotoluene
51.5
Benzoic acid
(80.2C)
147.2
Biphenyl
69.3
Biphenyl (69.3C)
120.4
Naphthalene
80.2
Diphenylacetic acid
(146.5C)
146.9
Benzil
94.7
Indium (156.6C)
28.7
Acetanilide
114.0
Tin (231.9C)
60.2
Benzoic acid
122.1
Diphenylacetic acid
146.5
Indium
156.6
Anisic acid
183.1
2-Chloro-anthraquinone
210.0
Tin
231.9
Anthraquinone
284.5
Lead
327.5
Zinc
418.9
METTLER TGA-850
With autosampler
Heating rate 20 K/min
3.2 %
9
0.063%
1.97%
2.02, 1.94, 2.03, 2.00, 1.99,
1.98, 1.99, 1.96, 1.82
PERKIN-ELMER TGA-7
Manual
Heating rate 20 K/min
2.1%
7
0.040%
1.93%
1.94, 1.90, 1.93, 1.94, 1.86, 1.99,
1.92
2.13% (n=1)
2.05% (n=1)
1.97% (n=9)
1.99% (n=1)
1.93% (n=7)
1.97 %
2.03 %
Not detectable
Weight 20 mg
0.1%
Consequences of seeds
of B
Weight 2 mg
If no seeds of B: no change
5 years at RT or 6 months
at 50 oC
Presence de B => catalysis
ex:
initial: appr.1%
1 day 50 oC : 10% B
Comparison of X-ray/DSC
Theoretical
amount (spiked)
13.6%
19.7%
29.2%
49.6%
58.5%
79.4%
Samples
1
2
3
4
5
6
7
8
Found X-ray
Found DSC
18%
18%
21%
46%
54%
80%
Found X-ray
97%
91%
92%
84%
83%
73%
60%
24%
21%
21%
26%
47%
50%
74%
Found DSC
79%
71%
90%
64%
85%
82%
27%
27%
Active ingredient
% of theoretical value
Capsule
Drug substance
98.0 %
(n = 10)
Capsule
Mannitol
97.1 %
(n = 1)
Capsule
10 mg
50 mg
Drug substance in
development
98.2 %
100.0 %
(n = 1)
(n = 1)
Doliprane tablet
Paracetamol
101.0 %
(n = 1)
Haldol tablet
Haloperidol
94.0 %
(n = 10)
Pellet batch 1
Saccharose
100.1 %
(n = 1)
Visken tablet
Pindolol
98.0 %
(n = 1)
Aknowledgment
Miriam Bellus
Thomas Buser
Stephanie Garnier
Christiane Goldbronn
Michael Mutz
Sabine Pfeffer
Philippe Piechon
Philippe Schwab
Gerard Sippel
Flora Zamman