Quality Assurance in Titration

Quality Assurance in Titration & Karl Fischer
Titration
or how to achieve reproducible results in titration
Titration Seminar 2014
Bettina Straub-Jubb
Product Management Inorganic Reagents
Merck Millipore / Lab Solutions
Merck KGaA, Darmstadt
Instrumental analysis
Agenda
Introduction in Titration
What for quality management on titration
Titration influence, titer determination a part of quality assurance
Volumetric solutions volumetric standards
Practical recommendations
Titration 2014 - Bettina Straub-Jubb
Why do we do titration?
With Titration do we determine quantitatively

the amount of a
component in our sample (e.g.

impurity)
purity of a substance (assay

determination)

3
Instruments
Titration
Karl Fischer Titration
The principle of titration

Volumetric solution in the
burette
Titration curve
Consumption of
vol. solution in ml
quantity of sample in mg
Sample or (volumetric standards)+ indicator

in water
End point is indicated mostly

through color change or
potential jump
5
Titration
2014 - Bettina Straub-Jubb
Titration reactions
Acidimetry
Acid Base titration
Proton transfer (Acid Base)
Alkalimetry
Bromatometry
Redox titration
Electron transfer (reducing agent oxidizing

agent)
Cerimetry
Iodometry
Ferrometry
Precipitation titration
Sparingly soluble (compounds precipitate)
Argentometry
Ions combine with molecules or other ions
Complexometric titration
forming
e.g. determine metals
soluble but only slightly dissociated complexes
Karl Fischer titration
special Titration for determine water
Karl Fischerr Titration
Use of titration - Applications

Assay determination
gives information about the purity of e.g. a raw material or substance
Determination of metal traces gives information

about the concentration of e.g. heavy metal impurities in raw materials,
products or other samples
Determination of concentrations
e.g. of the active ingredient of a drug
Determination of bromine index

e.g. to control the processes in the refineries and give a statement about
the quality of mineral oil products.
Determination of compounds
e.g. sulphurous acids in wine or acidity of wine
Water determination
0.01% - 100% water e.g in Kerosene
What can happen when titration analysis are

incorrect
Impurities in the products, food stuff, raw material, drugs
Production problems
Customer complains
What could be the reason for incorrect or not

expected results in titration?
The measuring equipment works incorrect (e.g. electrode, burette is defect)
The reagents for the analysis are out of the correct concentration
The standardisation is not correctly sufficient
The standard is not correct e.g. not dried before use, purity to low etc.
The sample preparation is wrong
The sample size
The calculation is wrong
The method is not exactly comparable and defined
The measuring temperature is different
The handling of the workers are different
The balance works incorrect or is not suitable
Not sufficient water for the dissolution of the sample
9
How can we avoid failures in titration?
with Quality Assurance
10
Measure to avoid failures?
Validation and regular monitoring of the titration equipment

(electrode, burette, etc.)
Definition of a constant temperature in the lab
Use of standardized volumetric solutions & Karl Fischer reagents
Use of primary or secondary reference materials as standards
Regular titer determination & instrument monitoring
Training of the lab personnel
Exact definition of the procedure (including sample preparation)
11
Quality assurance in titration
Validation
Qualification
Calibration
12
Qualification - Calibration
Calibration
Control of the accuracy of an instrument with a defined standard
Comparison of reference value and actual value
Qualification
Evidence that the measuring equipment works correct and fulfill the
expected results
13
Validation of titration system
Titration
Method
Titrator or
Burettes
Volumetric
Solution
14
Correct documentation
Who when what why
All this need to be documented!
Documentation with a ballpoint pen

No canceling, no over writing!
Sign all documents and mention the

correct date!
Clear & structured writing
15
Quality management in titration
Important preconditions are:

The use of reliable, accurate and qualified
reagents & standards
16
Which kind of requirement needs to be

fulfilled
Regulations (Pharmacopeias, FDA)
Numerous
norms, laws
and
regulations:
ONE
SYSTEM
DIN ISO 3771

National
Law
GMP
GLP
EN ISO 14001
ISO Guide 34
QM
ICH
Guidlines
ISO 17025
ASTM
ISO EN 9001ff
17
AOAC
Pharmacopeia requirements
Pharmacopoeia
general part
general regulations for using
the Ph. Eur.
description of general test
methods and reagents used for
analytical chemistry
Reag Ph Eur/ USP for analytical reagents

18
special part
with monographies of active
substances and auxiliaries
(raw materials) for pharmaceutical production.
Ph Eur / USP for raw materials and products
Pharmacopoeia and titration

Volumetric solutions for titration are described in chapter volumetric analysis in
the European Pharmacopoeia Part Reag Ph Eur. and in the USP under
Chapter reagents: volumetric solutions and volumetric standards
actual described methods
are not state of the art!
commercial available solutions and standards can be used!

Validations and qualification of the method
Beside instrument qualification

19
European
Pharmacopeia
20
21
Standardisation
22
Description of the
preparation of a
volumetric solutions
in the European
Pharmacopeia
23
Accuracy of titration results how??
Titration
24
Titration results are influenced by

Titration instrument
Method
Titer
Reagents
Laboratory conditions
25
How can we correct such measurement

influences?
26
with a titer determination!
27
Is a titer determination always necessary?

Even if working under strict QM requirements or
according Pharmacopeias and other regulations
and expect quite accurate results of +/-1% relative!
Note: the titer is a correction factor
28
The titer determination corrects

equipment error (state of measuring systems)
burette error need to be calibrated regularly
electrodes error need to be qualified
handling differences (e.g. preparation of dilutions, different persons)
sample weight error (weighing error of the balance) need to be calibrated
temperature differences in the lab from the standardization temperature of the
solution
reagents concentration changes
If the titer is to far away from 1, trouble shooting is necessary!

Define for you laboratory the accepted titer range!
29
How should a titer determination carried out?
The titer determination of a volumetric solutions is usually done

with a volumetric standard.
Is it not possible to trace back a volumetric solution

directly to a volumetric standard, then it is
recommended to use a other volumetric solution which one
is directly measured against a volumetric standard
30
Certipur Volumetric Standards
Volumetric standards
are characterized by an exactly defined assay
directly traceable against SRM from NIST
Example:
Potassium hydrogen phthalate
31
Titration
acc. to USP and EN

reference material for titration standardization
Designation
of the standard
Assay
NIST
Traceability
USP & Ph Eur hint
Treatment before use
Titration
32
Certipur volumetric standards

Catalogue
no
Designation
Assay
in %
According to
Reag Ph Eur =
1 and USP=2
Application
1024050080
Sodium carbonate
99,80
Acidimetry
1024080080
Tris(hydroxymethyl)aminoethane
99,85
Acidimetry
1024000080
Potassiun hydrogen phtalate
99,80
1,2
Alkalimetry
1024010060
Benzoic acid
99,80
1,2
Alkalimetry
1024060080
Sodium chloride
99,85
1,2
Argentometry
1024090100
Zinc
99,90
Complexometry
1024100050
Calcium carbonate
99,90
Complexometry
1024040080
Potassium iodate
99,70
Not in 1 and 2
Iodometry
1024020080
Iron(II)ethylendiammonium sulfate
99,80
Not in 1 and 2
Redox titration
1024030080
Potassium dichromate
99,90
Redoxtitration
1024070060
Di-sodium oxalate
99,70
Redox titration
33
Support - Booklet for Titer Determination
Booklet how to do a titer determination pdf
Guideline how to perform a titer

determination of a volumetric solution!
34
Titration
Volumetric solutions
Titrisol concentrates
for more flexibility
About 40 products
Titripur ready to use

solutions in bottles for
determination of
assays, impurities and
components
About 70 products
Titripur readyto use

solutions in Titripac
a sophisticated
unique Merck
package for
determination of
assays, impurities and
components
About 20 products
Volumetric solutions are now measured in an DIN EN ISO /IEC

17025 accredited lab
35
Easy handling
For titration use, the Titripac can be directly connected with the titrator!
Tube
Tap must be opened

during Titration
Adapter from Merck
Screw
Screw
Burette
36
Titripac there is a difference

Inflexible bag in
the box systems
or PE bottles
Titripac EMD Millipore
Disadvantage 1: Inner bag is not flexible
Advantage 1: flexible inner bag
Air bubbles can enter the bag after a while
No risk of contamination
Risk of contamination
Air bubbles cannot enter the bag
Change of titer
Stable titer during shelf life
Disadvantage 2: Tap is not integrated
Advantage 2: Tap already installed
Contamination source
No contamination source
Direct connection to the titrator
37
Titration
Conclusion Titration
Titration for
- assay determination
- impurity determination
Correct Titration results only with a frequent titer determination

Titer determination only with volumetric standards
Titration results are influenced by
Instrument/burette
Volumetric solution
Laboratory conditions/temperature
Titration method
38
39
Titration Practical Recommendations | May 2014 Bettina Straub-Jubb
How often should I do a titer determination?

depends from:
the stability of the volumetric solutions
the expected accuracy
the conditions in the lab (temperature)
the packaging material of the volumetric solution
Unstable volumetric solutions require a more frequent factor determination (e.g.
diammonium iron(II)-sulfate solution, EDTA/Titriplex solutions)
In the case volumetric solutions containing organic solvents (e.g. alcohols, acetic
acid, Perchloracid), frequent determinations of the titer are necessary,
especially in non- air conditioned laboratories, because of a high temperture
influence
error ca. 0.1 % proC, aqueous solutions ca. 0,02 % pro C
The concentration change more frequently in alkaline solution because of CO2

influence from the environment
40
Correction formula for organic volumetric

solutions from Pharmacopeia
41
How to find out the frequency of a titer

determination
1. Make a titer determination for about 6 to 8 weeks daily
2. Check the stability
3. Reduce the titer determinations to the time the titer is stable
Note:
One titer determination is no titer determination!
For correct results minimum 3 better 6 titer determinations need to
be done.
Determination of the standard deviation.
42
Avoid CO2 contamination

to prevent alkaline solutions from CO2
use sodium hydroxide on a supporter
(granulated).
catalogue no.: 101564.0250
or use Titripac
43
Alkaline solutions affect glas bueretts

In alkaline solutions or EDTA solutions, the titer can
also change through chemical/mechanical wear of the
burette used.
Deviation of 0,8 % relative per year!
The testing of the burette is necessary
from time to time or the change of the burette!
44
Consumption of burette volume and sample

size
is important that the volume of
the burette is utilized!
to the sample size and to the burette size
50 ml burette: use 50 90 % of the burette volume
Refilling a burette during a titration should be avoided!
It can lead to signal instability or irregularities
in the curve profile
Lower consumption of volumetric solutions and a lower sample sizes
leads to a lower accuracy.
45
Gravimetric/volumetric aliquotting
Gravimetric aliquotting is always to be preferred before volumetric!
It is about a factor 10 more accurate
It depends solely on the accuracy of the balance
It is temperature independent
It is independent of volume measuring apparatus
For volumetric solutions with concentrations < 0,1 mol/l
it is to be recommended that instead of using a smaller weighed
sample the preparation of a volumetric standard solution of greater
volume should be prepared, with subsequent gravimetric aliquotting.

Page 46
Example for a titer determination of

NaOH 0.1 mol/l
Determination of the NaOH content
Acid-base titration / alkalimetry
Direct titration
Volumetric standard: potassium hydrogen phthalate
Direct weighing
Visual with phenolphthalein (colourless-faint pink)
Potentiometrical with a titrator
to be recommended, if the solution is used to titrate weak acids

Page 47
Example for a titer determination of

NaOH 0.1 mol/l
Determination of the total content of alkali (hydroxide and
carbonate)
Acid-base titration / Acidimetry
Direct titration
Hydrochloric 0,1 mol/l tested against tris(hydroxymethyl)-aminomethane
Volumetric (using the burette provided for the sodium hydroxide solution)
Visual with indicator acc. to Mortimer (blue-red)
Potentiometrical with a titrator
to be recommended when bases are to be used for strong acids

Page 48
Further practical advises
Close bottles always after use

Homogenization of the solution in the morning
(drops on the wall of the bottle)
Don't fill the solution out of the original bottle
connect it with the instrument directly
Do not use a drying agent for aqueous solutions
Regular calibration of electrodes for acid base titration with
buffer solutions very important for endpoint titrations
49
Conclusion
Quality assurance starts with the sample preparation and ends with
the interpretation of the result.
Correct Titration results only with a frequent titer determination
The following factors influence the accuracy of the result:
Sample preparation
Reference materials
Measuring method
Instruments
User itself
Each user has to determine which accuracy he expects and

accordingly adapt his procedure to achieve this .

Page 50

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Quality Assurance in Titration & Karl Fischer

What for quality management on titration

Titration influence, titer determination a part of quality assurance

Volumetric solutions volumetric standards

Titration 2014 - Bettina Straub-Jubb

With Titration do we determine quantitatively

component in our sample (e.g.

purity of a substance (assay

Titration 2014 - Bettina Straub-Jubb

Titration 2014 - Bettina Straub-Jubb

The principle of titration

Sample or (volumetric standards)+ indicator

End point is indicated mostly

Acid Base titration

Proton transfer (Acid Base)

Electron transfer (reducing agent oxidizing

Sparingly soluble (compounds precipitate)

Ions combine with molecules or other ions

e.g. determine metals

soluble but only slightly dissociated complexes

Karl Fischer titration

Titration 2014 - Bettina Straub-Jubb

special Titration for determine water

Karl Fischerr Titration

Use of titration - Applications

Determination of metal traces gives information

Determination of bromine index

What can happen when titration analysis are

Titration 2014 - Bettina Straub-Jubb

What could be the reason for incorrect or not

Titration 2014 - Bettina Straub-Jubb

How can we avoid failures in titration?

with Quality Assurance

Titration 2014 - Bettina Straub-Jubb

Measure to avoid failures?

Validation and regular monitoring of the titration equipment

Titration 2014 - Bettina Straub-Jubb