Thermal Analisys Pharmaceuticals

8/9/2019 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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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

- -

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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TA user meeting D. GironChemical & Analytical Development

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

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Thermal Analisys Pharmaceuticals