Thermal Analysis and Combined

techniques in pharmaceutical
industry
D. Giron, Chemical and Analytical Development,
Novartis Pharma Basel

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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

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Overview of pharmaceutical process

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Drug substances and excipients

Identification, melting, thermodynamic data

Single techniques: DSC, calorimetry, TG, TMA

Polymorphism
Investigation, choice of the salt form, manufacture, control
of crystallization, drying, milling, batch control

DSC, solution calorimetry, microcalorimetry, sub-ambient

DSC, TG, Variable temperature spectroscopy (IR, NMR,
Raman, X-ray), Thermomicroscopy, IR, Ramanthermomicroscopy, TG-IR, TG-MS, DSC-X-ray, DTA-TG

Raw materials: storage conditions

DSC, TG, water sorption-desorption isotherms with

combined X-ray diffraction , or with microcalorimetry

Amorphous state
Temperature Tg and influence of moisture, excipients

DSC, MDSC, TG, TCS

Quantitation

DSC, microcalorimetry

Purity
Raw materials: purification, stability

DSC

Stability
Thermal decomposition, kinetics, compatibility, stability

DSC, TG, TG-MS, TG-IR, microcalorimetry

Polymers
Characterization, miscibility, control, stability

DSC, TG, TMA, DMA, TG-MS, TG-IR, MDSC

Drug products
Physical interactions, phase diagrams

DSC

Process optimization: solid dispersions, solid solutions,

microspheres, modified release, lyophilisates

DSC, DSC-spectroscopy, DSC-X-ray, thermomicroscopy

IR, Raman, Electronmicroscopy

Drug products: control of processes, granulation, mixing,

milling, tabletting, spray-drying, kneading, melting,
lyophilization

DSC, solution calorimetry, microcalorimetry, sub-ambient

DSC, TG, Variable temperature spectroscopy (IR, NMR,
Raman, X-ray), Thermomicroscopy, IR, Ramanthermomicroscopy, TG-IR, TG-MS, DSC-X-ray, DTA-TG

Melting point of liquid formulations

Sub-ambient DSC

Identification, quantitation

DSC, TG

Water interaction in gels, creams, polymers

DSC, sub-ambient DSC, DSC-microscopy, DSC-X-ray,

DSC-TG, Electronmicroscopy

Characterization hydrated phospholipid bilayer

DSC, microcalorimetry

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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
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Determination of melting point and melting enthalpy,

example different salts

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Solid State/Definitions

Polymorphism is the ability of a compound to

crystallise into different crystalline states. Polymorphs
show the same properties in the liquid or gaseous
state but behave differently in the solid state.
Pseudo-polymorphism: a new compound is formed
between volatile solvent => solvates, hydrates.
The amorphous state is a non-ordered random solid
system.

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Energy diagrams
Enantiotropy

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Monotropy

Polymorphism and Kinetic, as examplified by DSC curves

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Reversible enantiotropic transition

Tolbutamide: reversibility followed by DSC and temperature
resolved X-ray diffraction

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Monotropic exothermic transition followed by X-ray

diffraction, IR and Raman

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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.

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Oxybuprocaine hydrochloride. XRD before and after the endothermic peak B =>A

B ->A 150oC

Form B

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MKS492: 6 crystallin forms

Solvent mediated transitions in B
Characteristic

Form A

Form B

Form B

Form C

Form D

DSC onset

111 oC

128 oC

118 oC

109 oC

Melting enthalpy J/g

93

981)

92

89

65

Transition heat J/g

<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)
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0.18

Manufacturing solid phases in situ using DSC

Example of propyphenazone

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Solution microcalorimetry H transition = HAsol - HBsol

H transition by Solution microcalorimetry = 9.7 kJ mol-1

H transition by DSC= 10.4 kJ mol-1
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Phase diagrams of solvates/Hydrates

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Examples of DSC/TG of solvates

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Solvates / Hydrates
Influence of experimental conditions

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Melting A
DSC

Ethanol solvate

Solvates. Use of TG-MS and

temperature resolved X-ray

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

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170C

Water sorption/desorption combined with moisture-X-ray diffraction

Hygroscopicity and polymorphs

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Solvate => hydrate not tightly bound

Thermogravimetry and discrimination between hydrated

forms

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Tetracaine. HCl
Relationships between all forms

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Use of combined TG-IR for the study of Aspartam

Step 1: dehydration, Step 2: cyclisation with loss of methanol

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Degradation demonstrated by combined

techniques
Melting A
DSC

Degradation
lactam + water

BA

Temperature resolved X ray

TG-MS

Loss of
water
m = 18

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lactam

185 C

150 C

120 C

FT-IR in heating cell

Degradation in lactam
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form B<=> form A

Interpretation of DSC,TG by TG-MS and

Temperature resolved X-ray and IR

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DSC and ist use for quality control

Comparison of quality of a raw
material of synthesis

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Comparison of a ney synthesis

Detection of instability by DSC: sample stored at

different temperatures and humidity

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Determination of freezable water by sub-ambient DSC

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Study of hydrates by sub-ambient DSC combined with TG

and X-ray diffraction
Sub-ambient DSC => freezable water, TG => total water
a) DSC of drug substance b) DSC of drug substance at 92%RH
c) DSC of drug substance suspended in water
Calculation of bound water: 3.5%, monohydrate: 3.5%

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Study of polymers and behaviour in drug products

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Phase diagrams of solid dispersions with

polyethylenglycols
Darodipine, same curves,
independently on the manufacture

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Influence of the manufacture: new

polymorphic form by co-melting procedure

Identification of polymorphs

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Dissociation of an hydrochloride salt into the

base in a gelatine capsule

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Examples of standard substances used for

calibration of DSC
Certified substances
Iodobenzene

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

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Example of validation of thermogravimetry

Precision
Batch 87902
Relative standard deviation, srel
Number of determinations, n
Absolute standard deviation, sabs
Mean value:
Individual values (%):
Influence of heating rate
5 K/min
10 K/min
20 K/min
Accuracy comparison of methods
TG at 20 K/min, n = 19
Water Karl Fischer
Solvents GC

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

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Sensivity of DSC <0.1 % B

Weight 20 mg

0.1%

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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

Determination of amorphous content

DSC: linearity r = 0.99, LOD= 1%
X-ray: linearity r = 0.99, LOD= 5%

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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%

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Use of microcalorimetry for the determination of amorphous content

Under high water vapour, the Tg of amorphous substances

decreases and crystallization is followed by isothermal
microcalorimetry
Transformation confirmed by X-ray diffraction
Limits of 1% or less easy to attain
Temperature, RH level, amount of analyte to be optimized

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Quantitation in drug product by DSC

Product

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)

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Aknowledgment
Miriam Bellus
Thomas Buser
Stephanie Garnier
Christiane Goldbronn
Michael Mutz
Sabine Pfeffer
Philippe Piechon
Philippe Schwab
Gerard Sippel
Flora Zamman

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