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Thermal Analysis and Combined

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

Chemical & Analytical Development
TA user meeting D. Giron

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

Chemical & Analytical Development
TA user meeting D. Giron

Overview of pharmaceutical process

Chemical & Analytical Development
TA user meeting D. Giron

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

Chemical & Analytical Development
TA user meeting D. Giron

DSC/Hot stage microscopy. Giron . • 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.Combined techniques • DSC or microcalorimetry and TG sensitive but not specific. TG/IR. TG/GC • Use of microcalorimetry Chemical & Analytical Development TA user meeting D. DSC/X-ray • DVS/X-ray. TG/MS. DSC/IR or Raman microscopy. no artefact • Combined DSC/TG.

Determination of melting point and melting enthalpy. Giron . example different salts Chemical & Analytical Development TA user meeting D.

Giron . Chemical & Analytical Development TA user meeting D. Polymorphs show the same properties in the liquid or gaseous state but behave differently in the solid state. hydrates. • Pseudo-polymorphism: a new compound is formed between volatile solvent => solvates. • The amorphous state is a non-ordered random solid system.Solid State/Definitions • Polymorphism is the ability of a compound to crystallise into different crystalline states.

Energy diagrams Enantiotropy Chemical & Analytical Development TA user meeting D. Giron Monotropy .

as examplified by DSC curves Chemical & Analytical Development TA user meeting D. Giron .Polymorphism and Kinetic.

Giron .Reversible enantiotropic transition Tolbutamide: reversibility followed by DSC and temperature resolved X-ray diffraction Chemical & Analytical Development TA user meeting D.

Monotropic exothermic transition followed by X-ray diffraction. IR and Raman Chemical & Analytical Development TA user meeting D. Giron .

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. Chemical & Analytical Development TA user meeting D. Giron .

Giron . XRD before and after the endothermic peak B =>A B ->A 150oC Form B Chemical & Analytical Development TA user meeting D.Oxybuprocaine hydrochloride.

2 20 oC in % (w/w) Chemical & Analytical Development TA user meeting D.5% Density g/cm3 1.5% 2% needles Plates/needles < 0.5% Morphology needles needles TG after 1 day at 92% RH < 0. Giron - - 0.18 .5% < 0.17 0.5% <0.27 0.400 1.112 oC Temperature Weight loss by TG <0.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 - 6 - - <0.422 1.411 Solubility water 0.5% >2% 108.

Giron .Manufacturing solid phases in situ using DSC Example of propyphenazone Chemical & Analytical Development TA user meeting D.

7 kJ mol-1 ∆H transition by DSC= 10. Giron .4 kJ mol-1 Chemical & Analytical Development TA user meeting D.Solution microcalorimetry ∆H transition = ∆HAsol .∆HBsol ∆H transition by Solution microcalorimetry = 9.

Giron .Phase diagrams of solvates/Hydrates Chemical & Analytical Development TA user meeting D.

Giron .Examples of DSC/TG of solvates Chemical & Analytical Development TA user meeting D.

Solvates / Hydrates Influence of experimental conditions Chemical & Analytical Development TA user meeting D. Giron .

Giron 170°C . Use of TG-MS and temperature resolved X-ray Solvate -> C C -> A Acetone solvate 40°C TG Ethanol solvate 40°C m = 46 Melting A Acetone solvate DSC 125°C 125°C Solvate -> C C ->A 170°C TG m = 58 Chemical & Analytical Development TA user meeting D.Melting A DSC Ethanol solvate Solvates.

Water sorption/desorption combined with moisture-X-ray diffraction Hygroscopicity and polymorphs Chemical & Analytical Development TA user meeting D. Giron Solvate => hydrate not tightly bound .

Thermogravimetry and discrimination between hydrated forms Chemical & Analytical Development TA user meeting D. Giron .

Tetracaine. Giron . HCl Relationships between all forms Chemical & Analytical Development TA user meeting D.

Use of combined TG-IR for the study of Aspartam Step 1: dehydration. Step 2: cyclisation with loss of methanol Chemical & Analytical Development TA user meeting D. Giron .

Degradation demonstrated by combined techniques Melting A DSC Degradation → lactam + water B→A Temperature resolved X ray TG-MS Loss of water m = 18 Chemical & Analytical Development TA user meeting D. Giron lactam →185 °C A →150 °C B →120 °C .

Giron form B<=> form A .FT-IR in heating cell Degradation in lactam Chemical & Analytical Development TA user meeting D.

Interpretation of DSC.TG by TG-MS and Temperature resolved X-ray and IR Chemical & Analytical Development TA user meeting D. Giron .

Giron Comparison of a ney synthesis .DSC and ist use for quality control Comparison of quality of a raw material of synthesis Chemical & Analytical Development TA user meeting D.

Detection of instability by DSC: sample stored at different temperatures and humidity Chemical & Analytical Development TA user meeting D. Giron .

Determination of freezable water by sub-ambient DSC Chemical & Analytical Development TA user meeting D. Giron .

5%. Giron .5% Chemical & Analytical Development TA user meeting D. 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. monohydrate: 3.Study of hydrates by sub-ambient DSC combined with TG and X-ray diffraction Sub-ambient DSC => freezable water.

Giron .Study of polymers and behaviour in drug products Chemical & Analytical Development TA user meeting D.

Phase diagrams of solid dispersions with polyethylenglycols Darodipine. Giron Influence of the manufacture: new polymorphic form by co-melting procedure . independently on the manufacture Chemical & Analytical Development TA user meeting D. same curves.

Giron .Identification of polymorphs Chemical & Analytical Development TA user meeting D.

Dissociation of an hydrochloride salt into the base in a gelatine capsule Chemical & Analytical Development TA user meeting D. Giron .

5 Lead 327.5 Benzoic acid (80.1 Diphenylacetic acid 146.2 Benzoic acid 122.3 Biphenyl (69.2 Diphenylacetic acid (146.7 Indium (156.0 Tin (231.2°C) 147.Examples of standard substances used for calibration of DSC Certified substances Iodobenzene Onset T (°C) certificate -31.7°C) 112.5 Zinc 418.6°C) 28.2°C) ∆H (J/g) 148.5 Indium 156.9 Chemical & Analytical Development TA user meeting D.9°C) 60.0 Tin 231.3 Standard Substance Naphthalene (80. Giron .6 Anisic acid 183.6 H2O 0.5°C) 146.1 2-Chloro-anthraquinone 210.9 Benzil 94.7 Acetanilide 114.3°C) 120.9 Anthraquinone 284.4 Naphthalene 80.2 Biphenyl 69.0 Benzil (94.0 4-Nitrotoluene 51.

99. 1. 1.99. 1. 2. 2.94. 1. n Absolute standard deviation. 1.98.93% 1.93% (n=7) 1.1% 7 0.Example of validation of thermogravimetry Precision Batch 87902 Relative standard deviation.063% 1. 1. 1.92 2.03.90. 1. Giron .02.96.93.2 % 9 0.97% 2.040% 1.00. 1. 1.86. srel Number of determinations.99.94. 1.97% (n=9) 1.82 PERKIN-ELMER TGA-7 Manual Heating rate 20 K/min 2.13% (n=1) 2.94.05% (n=1) 1. n = 19 Water Karl Fischer Solvents GC METTLER TGA-850 With autosampler Heating rate 20 K/min 3.99% (n=1) 1.97 % 2. 1.03 % Not detectable Chemical & Analytical Development TA user meeting D. 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.

1% Chemical & Analytical Development TA user meeting D.1 % B Weight 20 mg B 0.1% 1 day 50 oC : 10% B .Sensivity of DSC <0. Giron Consequences of seeds of B Weight 2 mg B If no seeds of B: no change 5 years at RT or 6 months at 50 oC Presence de B => catalysis ex: initial: appr.

Determination of amorphous content DSC: linearity r = 0.99.99. Giron . LOD= 1% X-ray: linearity r = 0. LOD= 5% Chemical & Analytical Development TA user meeting D.

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% Chemical & Analytical Development TA user meeting D.5% 79.7% 29. Giron .6% 58.Comparison of X-ray/DSC Theoretical amount (spiked) 13.2% 49.6% 19.

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. Giron .Use of microcalorimetry for the determination of amorphous content • • • • Under high water vapour. amount of analyte to be optimized Chemical & Analytical Development TA user meeting D.

0 % (n = 10) Capsule Mannitol 97.2 % 100.Quantitation in drug product by DSC Product Active ingredient % of theoretical value Capsule Drug substance 98.0 % (n = 10) Pellet batch 1 Saccharose 100.0 % (n = 1) Chemical & Analytical Development TA user meeting D.0 % (n = 1) Haldol tablet Haloperidol 94.1 % (n = 1) Visken tablet Pindolol 98.0 % (n = 1) (n = 1) Doliprane tablet Paracetamol 101. Giron .1 % (n = 1) Capsule 10 mg 50 mg Drug substance in development 98.

Giron .Aknowledgment Miriam Bellus Thomas Buser Stephanie Garnier Christiane Goldbronn Michael Mutz Sabine Pfeffer Philippe Piechon Philippe Schwab Gerard Sippel Flora Zamman Chemical & Analytical Development TA user meeting D.