Thermal Analisys Pharmaceuticals
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Transcript of Thermal Analisys Pharmaceuticals
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TA user meeting D. Giron
Chemical & Analytical Development
Thermal Analysis and Combinedtechniques 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 combinedtechniques
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, Raman-
thermomicroscopy, 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, Raman-
thermomicroscopy, 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 notspecific.
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. Polymorphsshow the same properties in the liquid or gaseousstate but behave differently in the solid state.
Pseudo-polymorphism: a new compound is formedbetween volatile solvent => solvates, hydrates.
The amorphous state is a non-ordered random solidsystem.
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Energy diagrams
Enantiotropy Monotropy
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Chemical & Analytical Development
Polymorphism and Kinetic, as examplified by DSC curves
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Reversible enantiotropic transition
Tolbutamide: reversibility followed by DSC and temperatureresolved 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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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
Temperature
- 6
108- 112 oC
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Weight loss by TG
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Manufacturing solid phases in situ using DSCExample 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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Solvates. Use of TG-MS and
temperature resolved X-raySolvate -> C
DSC
TG
m = 46
C -> A
Melting A
170C
125C
40C 40C
125C
170C
Solvate -> C
C ->A
m = 58
Melting ADSC
TG
Ethanol solvate
Acetone solvate
Acetone solvate Ethanol solvate
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Water sorption/desorption combined with moisture-X-ray diffraction
Hygroscopicity and polymorphs Solvate => hydrate not tightly bound
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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
TG-MS Temperature resolved X ray
BA
Melting A
Degradation
lactam + water
DSC
m = 18
Loss of
water
185C
150C
120CB
A
lactam
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FT-IR in heating cell
Degradation in lactam form B form A
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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 rawmaterial of synthesis
Comparison of a ney synthesis
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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 TGand 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 withpolyethylenglycols
Darodipine, same curves,
independently on the manufacture
Influence of the manufacture: new
polymorphic form by co-melting procedure
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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 DSCCertified substances Onset T (C)
certificateStandardSubstance
H (J/g)
Iodobenzene -31.3 Naphthalene(80.2C)
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) 60.2Benzoic 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 METTLER TGA-850With autosampler
PERKIN-ELMER TGA-7Manual
Batch 87902 Heating rate 20 K/min Heating rate 20 K/min
Relative standard deviation, srel 3.2 % 2.1%Number of determinations, n 9 7
Absolute standard deviation, sabs 0.063% 0.040%
Mean value: 1.97% 1.93%
Individual values (%): 2.02, 1.94, 2.03, 2.00, 1.99,
1.98, 1.99, 1.96, 1.82
1.94, 1.90, 1.93, 1.94, 1.86, 1.99,
1.92Influence of heating rate
5 K/min 2.13% (n=1)
10 K/min 2.05% (n=1) 1.99% (n=1)
20 K/min 1.97% (n=9) 1.93% (n=7)
Accuracy comparison of methodsTG at 20 K/min, n = 19 1.97 %
Water Karl Fischer 2.03 %
Solvents GC Not detectable
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Sensivity of DSC catalysis
ex:
initial: appr.1%1 day 50 oC : 10% B
D t i ti f h t t
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Determination of amorphous content
DSC: linearity r = 0.99, LOD= 1%X-ray: linearity r = 0.99, LOD= 5%
C i f X /DSC
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Theoreticalamount (spiked)
Found X-ray Found DSC
13.6% 18% 21%
19.7% 18% 21%
29.2% 21% 26%49.6% 46% 47%58.5% 54% 50%
79.4% 80% 74%
Samples Found X-ray Found DSC
1 97% 79%2 91% 71%
3 92% 90%4 84% 64%
5 83% 85%
6 73% 82%7 60% 27%
8 24% 27%
Comparison of X-ray/DSC
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Use of microcalorimetry for the determination of amorphous content
Under high water vapour, the Tg of amorphous substancesdecreases and crystallization is followed by isothermalmicrocalorimetry
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
Capsule
Capsule 10 mg
50 mg
Doliprane tablet
Haldol tablet
Pellet batch 1
Visken tablet
Drug substance
Mannitol
Drug substance in
development
Paracetamol
Haloperidol
Saccharose
Pindolol
98.0 % (n = 10)
97.1 % (n = 1)
98.2 % (n = 1)
100.0 % (n = 1)
101.0 % (n = 1)
94.0 % (n = 10)
100.1 % (n = 1)
98.0 % (n = 1)
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Aknowledgment
Miriam Bellus
Thomas Buser
Stephanie GarnierChristiane Goldbronn
Michael Mutz
Sabine Pfeffer
Philippe Piechon
Philippe Schwab
Gerard Sippel
Flora Zamman