handling difficult samples in karl fischer analysis
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Handling Difficult Samples in Karl Fischer Analysis
Background
• Analysis of moisture is becoming increasingly important to many different industries
• Many of these reasons require not only a precise, but also accurate reading
• For years, most moisture analyses have been conducted on a semi-quantitative or even qualitative level
Questions about how much water? Karl Fischer analysis is the answer.• Karl Fischer (KF) titrations have been the gold standard for water
analysis since 1935
• The KF titration provides a reliable and robust way to directly analyze for water in a sample
• Many other techniques exist for indirect analysis of water in a sample, but KF titration is the best way to calibrate this other methodology
• KF is rapid, well characterized, and the recognized standard for water analysis in many solids, liquids and semi-solids
CH3OH + SO2 + RN → (RNH)SO3CH3 H2O + I2 + (RNH)SO3CH3 + 2 RN → (RNH)SO4CH3 + 2 (RNH)I
Measurement range
% range ppm range
Volumetric KF titration Coulometric KF titration
Volumetric KF titration
Direct addition of reagents by burette to
sample in methanol
Typical volumetric KF titrator
Coulometric KF titration
In situ generation of iodine by electrical means
Typical coulometric KF titrator
Most KF systems I see can only handle one sample at a time!
Coulometric KF
Volumetric KF
Karl Fischer reaction
CH3OH + SO2 + RN (RNH)SO3CH3 H2O + I2 + (RNH)SO3CH3 + 2 RN (RNH)SO4CH3 + 2 (RNH)I
Hydroxide, Carbonate
Reducing agent
Oxidant
Silanol
Acid Acid / Base
Ketone / Aldehyde Aldehyde
Side reactions
• Acids
• Bases
• Aldehydes and ketones
• Carbonates, hydroxydes and oxides
• Silanol / Siloxane
• Strong reducing agents
• Strong oxidizing agents
KF titration curve
Fast release of waterSlow release of water
~130 s ~290 s
How do we mitigate side reactions, poor water release and gaseous samples?
• Adjust pH with buffers• Use specialized reagents for
aldehydes and ketones• Use different sample preparation
What if my sample comes in a container that looks like this?
KF Gas Analyzer
• For determining water in:
• Propane• Propene• LPG• LNG• Butane• Butene• Butadiene• Dimethyl ether• Ethylene oxide• Methylene chloride• Ethylene chloride• Vinyl chloride• Chlorofluorocarbons
• Analyzes gases and liquefied gases from sample cylinders!
Mass Flow ↙ Controller
← Oil Filter
Heater →
Precision← ControlValve
↙ Coulometer
Sample Inlet→
Nitrogen Inlet→
KF Gas Analyzer
Reproducibility
Results of 360 measurements of LPG (3 g per measurement) within 84 h, mean value: 26,5 µg/g ± 0,8 µg/g
y = -0,005x + 27,389
0
5
10
15
20
25
30
35
0 50 100 150 200 250 300 350
number of measurements
wat
er c
on
ten
t [µ
g/g
]
80°C / constant sample flow
50°C / constantsample flow
50°C / fluctuating sample flow
What if my sample is solid or liquid and needs a lot of preparation?
Gas extraction
1. Samples soluble in KF reagent
2. Samples that release water in KF compatible solubility promoters
direct titration gas extraction
1. Samples that are not soluble in KF reagent
2. Samples that cause side reactions
liquid extraction
1. Samples that release water in organic liquids
Principle of the Metrohm oven technique
Dry carrier gas is used to
transport evaporated humidity
into titration vessel
Universal to nearly all samples
Principle of the Metrohm oven technique
Metrohm developed the orginal
headspace analysis for Karl Fischer
titration
Advantages of using a KF Oven
• Nearly all KF analyses can utilize oven• Very economical
• Much smaller reagent use• Much more effective use of time
• Efficient• Automation to handle many samples without human
interaction• No need to clean vessel after just a few analyses
• Wide variety of applications• Nearly all KF samples can be adapted to oven
technique
Gas extraction (oven method)
• Step 1: (use empty vial)
- Heat up KF oven
- Start gas flow
- Titrate cell to dryness
• Step 2: (use empty vial)
- Determine blank value
• Step 3:
- Put sample vial into the oven
- Heat up sample and transfer released water with carrier
gas to KF cell
Gas extraction (oven method)
Sample: Motor oil
• Oven, 160°C, N2
Content: ~ 390 ppm
• Direct measurement
Content: ~ 960 ppmlong determination time
curve with side reaction
Headspace KF analysis
• Wonderful technique for most sample types• Until recently, Metrohm sample changers would
only accommodate a 6 mL headspace vial• Now Metrohm can adapt our 874 USB KF Oven
Sample Processor to fit many of the most common vials
How do you adapt a sample to KF Ovens?• Choose a temperature
• Classic method• Multiple samples with different temperatures• Choose best temperature for most stable and
reproducible moisture evolution• Optimize for speed
• Gradient Method• One sample over a range of temperatures
• Choose a carrier gas• Choose air, nitrogen or argon depending on the
thermal stability and combustibility of the sample
Example data: method development Classic method of temperature determination
• Steroidal compoundTemp. Air
sourceExtraction
TimeWater
ContentDecompositi
on?1 150 Air 300 0.04% Yes2 160 Air 300 4.44% Yes3 170 Air 300 6.60% Yes4 200 Air 300 6.91% Yes5 150 N2 300 0.14% Yes6 155 N2 300 0.98% Yes7 135 N2 1800 0.04% No8 140 N2 900 0.06% No
Temperature gradient
• What oven temperature is optimal for an unknown
sample?
• Find the ideal temperature running a temperature
gradient with the KF OVen
• Looking for a temperature that will accelerate
water extraction but not pyrolyze the sample • Pyrolysis or combustion leads to erroneously high results
Example data from temperature gradient analysis
• Sample of mixed sugars and buffers• Lyophilized Sample• Ran 50 – 180ºC in 30 minutes
Example data from temperature gradient analysis
• Chose temperature of 95 degrees• Analysis was slightly more than 7
minutes• This only took 1 gradient sample and one
sample to confirm• Without gradient, this takes up to 7
samples
Example data: method development Gas determination
• Steroidal compound
Air carrier gas at high temperatureEvidence of decomposition
Nitrogen carrier gas at low temperatureStable extraction
Headspace Karl Fischer moisture analysis in your vial • The 874 uses Metrohm’s
exclusive KF Oven technology for unsurpassed moisture results
• The 874 is perfect for your lyophilized samples because Metrohm USA will customize the 874 to fit your sample vial!
• Because only water vapor is analyzed, reagent costs are greatly reduced
• Holds up to 36 samples depending on rack configuration
Metrohm NIRSystemsPositive vibration
Reagent-free Moisture Analysis
Dr. Hari Narayanan Product Manager NIRS
Metrohm USA
Techniques for moisture analysis
Metrohm expands its portfolio to include Near Infrared Spectroscopy!
<<Green Chemistry>>
Designed by FOSSPowered by Metrohm
Techniques for moisture analysis
Why NIR for moisture analysis
• Requires no sample preparation• Non-destructive• Fast, accurate and precise• Multi component analysis• No solvent procurement or disposal• Low-cost analysis• Easy to use and maintain• Remote sampling via fiber optics
Secondary technique: requires primary method for calibration development
• Stretching
• Bending
symmetrical asymmetrical
scissoring rocking wagging twisting
NIR Spectroscopy
• 780nm to 2500nm• Overtones and Combination Bands
• Based on absorption in the Near Infrared region of the spectrum
• It provides both chemical and physical information
• Primarily sensitive to organic compounds
• O-H, C-H, N-H bonds absorb strongly in NIR
NIR spectroscopy
NIR spectrum
Combination
1st Overtone
2nd Overtone
3rd Overtone
NIR spectrum of water
Transmission spectrum of waterPathlength ~ 3 mm
Sampling in NIR
Samples Types
Reflectance: Solids, Granules, Powders…Trans-Reflectance: Pastes, Syrups…Transmission: Liquids, Films, Oils…Diffuse Transmission: Tablets, Softgels…
Analysis Types• Identification• Qualification• Quantification• Trend analysis – Determination of
Change• Process monitoring and Control
Identification & Qualification
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
1100 1300 1500 1700 1900 2100 2300 2500
Wavelength (nm)
Ab
so
rba
nc
e (
Lo
g 1
/R)
anhydrous lactose
lactose monohydrate
Water Bands
Run Samples
as Standards
in NIR
Analyze Samples
by Primary Method
Calibration and
Validation
Routine Analysis by NIR
Right Sampling ModuleSample
Presentation
Collection Paramete
r
Accuracy of Primary
method influences
NIR Method
Chemometric
Software
Method Maintena
nce
Quantitative Moisture analysis
Instrumentation Pre-dispersive
Post-Dispersive: Scanning and PDA
XDS Monochromator
Hot-swappable modules
Metrohm NIRSystems Family
Lab
NIRS XDSAnalyzer
NIRS XDS RapidCont
ent Analyzer (RCA)
NIRS XDS
RapidContent
Analyzer – Solids
NIRS XDS MultiVialAnalyzer
NIRS XDS
MasterLab
Analyzer
NIRS XDS SmartProb
eAnalyzer
NIRS XDS
Interactance
OptiProbe Analyzer
NIRS XDS Transmissio
nOptiPr
obe Analyz
er
NIRS XDS RapidLiquid Analyzer
(RLA)
NIRS DS2500Analyzer
Process
NIRS Analyzer PRO
NIRS Analyzer PRODirectLight/NonContact
NIRS Analyzer PROContactReflection
NIRS Analyzer PROFiberSystem
NIRS XDS Process Analyzer
NIRS XDS Process
Analyzer – SingleFiber SinglePoint
NIRS XDS Process
Analyzer – SingleFibe
r 4 Channels
NIRS XDS
Process Analyz
er – SingleFiber 9 Channe
ls
NIRS XDS Process
Analyzer – Microbundle SinglePoint
NIRS XDS Process
Analyzer – Microbund
le 4 Channels
NIRS XDS
Process Analyz
er – Microbundle 9 Channe
ls
NIRS XDS Process
Analyzer – DirectLight/NonContact
NIR Applications
• Pharmaceuticals• Chemicals• Petrochemicals• Polymers• Paper and Pulp• Textiles• Cosmetics• And more…
Moisture in polymer pellets
The water content of expandable polystyrene is determined according to Karl Fischer
The sample is first dissolved in p-xylene to extract the water
Then methanol is added to precipitate the sample
The water is determined in the supernatant solution by coulometric titration
Moisture in polymer pellets
NIRS DS2500 Analyzer: Sample Rotation
Moisture in polymer pellets
Moisture in polymer pellets
• MLR• R2 = 0.9988 • SEC = 0.5413
Lab Moisture %
NIR
Pre
dict
ed M
oist
ure
% NIR Advantage
• Speed and Simplicity• Reduce laboratory analysis • Provide increased process
performance • Quality assurance monitoring
Moisture in solvent and recovery streams
NIRS XDS RapidLiquid Analyzer
Moisture in solvent mixture
Moisture in solvent mixture
PLS: Factor 3 Correlation: 0.9998SEC: 0.1939
• Save Time & Money• NIR can be off-line, at-
line, or on-line
• NIR can measure Solvent components and moisture in single run
Inline Process NIRgranulator drying analysis
• Single-pot granulator dryer
• Probe in contact with powder
• Provides real-time process analysis and control
Granulator drying analysis
• Blend of lactose and starch granulated with 1.5% water and 8% methanol
• Granulation was dried with heat and vacuum
• NIR probe monitored drying in-process• NIR prediction models developed for water
and methanol
NIRS XDS Process Analyzer
Granulator drying spectra
1800 1850 1900 1950 2000-0.020
-0.016
-0.012
-0.008
-0.004
0.000
0.004
0.008
0.012
Granulator drying moisture analysis
Four factor PLS from 1800-2084nm R2= 0.99; SEC=0.022; SECV=0.024
Granulator drying moisture trend
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
5:16:48 5:24:00 5:31:12 5:38:24 5:45:36 5:52:48 6:00:00 6:07:12 6:14:24 6:21:36
Moi
stur
e %
Time
Blend #4 Moisture % vs Time
Granulator drying methanol analysis
Four factor PLS :1800-2084nm; R2=0.99; SEC=0.184; SECV=0.193
Granulator drying methanol trend
0
1
2
3
4
5
6
7
8
9
5:16:48 5:24:00 5:31:12 5:38:24 5:45:36 5:52:48 6:00:00 6:07:12
MeO
H %
Time
Blend # 4 MeOH % vs Time
Moisture analysis in a fluid bed dryer
Sampling
• Fluid bed dryer charged with lactose and MCC
• Spectra collected every 50 seconds
• LOD sample taken every 5 minutes
View of spoon probe
Spectra of dryer samples
Prediction model
2 Factors PLS1100 nm – 1650 nm,SEC = 0.7358 %, R2 = 0.9519.
Validation Example
SEP = 0.204 %
Trend chart of fluid bed
0 5 10 15 20 25 30 35 40 450
2
4
6
8
10
12
Time minutes
Moi
stur
e %
Moisture in lyophilized material
KFCalibrationValidation
NIRRoutine Samples
NIR instrumentation
• NIRS XDS Rapid Content Analyzer• Scan range
400–2500 nm• 32 scans/spectrum
Experimental design
• Lyophilized product• Contained in ~ 30 mL serum vials• Average cake weight is 1.6 g• Acceptable moisture limit is NMT 2 %
• Calibration sample set• 46 samples used to prepare training and test sets
• Near-IR analysis• Spectra of calibration samples collected in triplicate
• Primary analyses• Regression equations developed using data from
volumetric Karl Fischer titration
Raw NIR absorbance spectra
Calibration for low residual moisture
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
NIR
Pre
dict
ed (
% m
oist
ure)
Karl Fischer (% moisture)
NIR Predicted % Moisture = 0.806 - 19.411 A"
A"1844 nm
2124 nm
SEP = 0.119 R = 0.992
Comparison of NIR and LOD methods
LOD values were, on average, lower than NIR results by 0.20 ± 0.17 % H2O.
Conclusion
• NIR is well suited for analysis of residual moisture in lyophilized products
• Samples can be easily altered to provide calibration sets with varying amounts of moisture
• Regression equations should be optimized for the specific moisture range of interest
• The speed of the technique allows large sample sets to be analyzed, enabling NIR to be used either as a diagnostic or inspection tool
• Combined KF Thermoprep with NIR allows the quick calibration and validation
Summary• Combined Titration and NIR
• Calibration and Validation• Routine application
• Accuracy and calibration stability• Methods from lab to process • Flexible and customized sampling accessories• Rugged instrumentation• Continual technical and application support
Thank You
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