KARL - FISCHER Analysis: Water Content Determination

1. INTRODUCTION:

Karl Fischer was the scientist, who in 1935 developed the original Karl Fischer
method for water determination in various compounds.
Water content or moisture content needs to be determined at all stages of the
manufacturing process from raw materials to finished goods. Mostly it is determined in
Quality Control Labs, Process Labs, General Chemistry, R&D Labs, Analytical Labs and
Manufacturing department as quality of the product depends on it. In the pharmaceutical
industry, it is essential to know the amount of water contained in the ingredients of a drug in
order to correctly predict its lifetime, stability and effectiveness. In the food industry, the
water content of both raw materials and the finished foodstuff needs to be carefully
monitored.
The Karl Fischer titration is a direct method that is almost specific for water. The
method is especially useful for low moisture levels (<1%), and also levels <0.01% are
achievable.

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2. Theory of Karl - Fischer Technique:

A Karl Fischer titration determines the water content in a sample, based on an
iodine/iodide redox reaction. The titration is based on the oxidation of sulphur dioxide by
iodine in the presence of water. It is the same reaction as the iodometric titration of sulphur
dioxide in water. Titration may be defined as – “A technique to determine the concentration
of a substance in solution by adding to it a standard reagent of known concentration in
carefully measured amounts until a reaction of definite and known proportion is completed,
as shown by a color change or by electrical measurement, and then calculating the unknown
concentration.”
In this method, water reacts with iodine until the water is consumed and the
endpoint is reached. Overall reaction can be written as –

H2O + SO2 + I2 ↔ 2HI + SO3

or
2H2O + SO2 + I2 ↔2HI + H2SO4

In 1935, Karl Fischer published a description of “a new procedure for the titration of water”
using the above reaction in an anhydrous nonaqueous solvent. However, in order to shift the
equilibrium to the right, it was necessary to neutralise the acids produced. Originally
pyridine was used as the neutralising base. Later on, diethanolamine followed by imidazole
were used as buffers. Recent studies show that methanol, which is the most commonly used
solvent, contributes in the reaction. Ethanol-based reagents have recently emerged. These
have the advantage of being less toxic, offering more stable endpoints and faster kinetics.

Actually Karl Fischer reaction occurs in two stages:

(1) SO2 + CH3OH + B ↔ CH3SO3- + HB+

(2) CH3SO3- + H2O + I2 + 2B ↔ CH3SO4- + 2HB+ + 2I-

Where B = Base

Since water and I2 are consumed in equimolar amounts in reaction 2, if you know
the amount of I2 consumed, you know the amount of water that was present in the sample.

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3. Factors to consider in Karl – Fischer Titration:

A. pH considerations
The Karl Fischer reaction can only take place in a certain pH range between 5 and 7.
In this pH range, the reaction remains constant. If the pH drops too low, end point
attainment becomes sluggish or an end point will not be reached at all. If the pH is too high,
side reactions occur making the titration non-stoichiometric. We can therefore say that
errors occurring during a KF titration may be due to a change in the pH of the titration
solvent. Use acid, base, or buffer if necessary.

pH dependence of the Karl – Fischer reaction. [K = Reaction kinetic constant]

The pH of the titration solvent can be tested using a combined pH electrode and a
pH meter. The electrode is first calibrated with aqueous buffer solutions and afterwards the
pH of the titration solvent is measured.

Note: do not place the pH electrode directly into the KF cell because excessive moisture
will be introduced along with the electrode. For further information, consult the user’s
manuals of the main manufacturers of Karl Fischer reagents.

B. Aldehydes and ketones:

Use special reagents to prevent side reactions which generate or consume water and prevent
good endpoints

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C. Water content:
Consider when choosing auto-titrator.

D. Sample size:
Choose sample size that is large enough for precise determination but not so large as to
prolong the titration, exceed the capacity of the reagent, or be insoluble.
The sample size should be small so that as many samples as possible can be titrated in the
same electrolyte solution and the titration time kept short. However, take care that the
sample contains at least 50 μl water. The following table provides guidelines for the sample
weight:

Water content of Sample Sample size Water to be determined

100000 ppm = 10 % 50 mg 5000 µg
10000 ppm = 1 % 10 mg – 100 mg 100 µg – 1000 µg
1000 ppm = 0.1 % 100 mg – 1 g 100 µg – 1000 µg
100 ppm = 0.01 % 1g 100 µg
10 ppm = 0.001 % 5g 50 µg

E. Frequency of Solvent/Working Medium Change:

When the vessel is full, when the methanol content is <25%, when the capacity of the
solvent in exceeded (generally not more than 1 mg water per 1 ml methanol.)

F. Exclusion of background water:

Maintain desiccant tubes; keep reagents dry, good seals on instrument and reagent bottles

G. Pre-titration / conditioning of working solution:

Solvent/working solution must be dry but not over titrated before the sample titration to
avoid positive or negative bias to results.

H. Solubility of the sample:

Sample Solubility is Extremely Important to Obtain Total Water Content. Sample must be
completely dissolved prior to the start of the titration to obtain accurate and reproducible
results.
Total Water = Surface Water + Bound Water

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Different methods to improve sample solubility are:

i. Choose the right solvent
ii. Allow sufficient time for dissolution (extract time)
iii. Grind sample
iv. Co-solvent additions
v. Elevating solvent system temperature and
vi. Adding homogenizer to system.

I. Conductivity:
Conductivity of the solvent and added sample has to be sufficient to support proper function
of the electrodes in order to detect the endpoint and/or generate the iodine titrant. (by
coulometric type)

J. Influence of the Base:

Pyridine was the original Karl-Fischer base. Pyridine because of its weak basicity, cannot
totally neutralize the methylsulfurous acid. The equilibrium in reaction at stage-1 is not
completely shifted to the right. The reaction with pyridine is therefore slow and the
endpoint is not stable, often making the repeatability using pyridine very poor.

Pyridine Imidazole

Imidazole was chosen to replace pyridine as it shifts the reaction at stage-1

completely to the right, reaction is swift and endpoints clear and stable. Imidazole also does
not have the unpleasant odor and toxicity of pyridine.

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K. Stability of the Reagent:

The stability of the original Karl Fischer reagent initially prepared with an excess of
methanol was found to be fairly poor and hence, evidently needed frequent standardization.
However, it was established subsequently that the stability could be improved significantly
by replacing the methanol by 2-methoxyethanol. It has been observed that the titer of the
Karl Fischer reagent, which stands at 3.5 mg of water per milliliter of reagent, falls rapidly
upon standing with the passage of time. Hence, the following precautions must be observed
rigidly using the Karl Fischer reagent, namely:
(a) Always prepare the reagent a day or two before it is to be used,
(b) Great care must be taken to prevent and check any possible contamination either of the
reagent or the sample by atmospheric moisture,
(c) All glassware(s) must be thoroughly dried before use,
(d) Standard solution should be stored out of contact with air, and
(e) Essential to minimise contact between the atmosphere and the solution during the course
of titration.

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4. Types of Karl – Fischer titrations:

There are two determination methods different in iodine-providing principle:
(1) Volumetric titration method, and
(2) Coulometric titration method.
In the volumetric titration method, iodine required for reaction with water is
previously dissolved in water determination TS, and water content is determined by
measuring the amount of iodine consumed as a result of reaction with water in a sample. It
is good for high level moisture determination.
In the coulometric titration method, first, iodine is produced by electrolysis of the
reagent containing iodide ion, and then, the water content in a sample is determined by
measuring the quantity of electricity (Coulombs) which is required for the electrolysis (i.e.,
for the production of iodine), based on the quantitative reaction of the generated iodine with
water. It is good for low level moisture determination.

�Volumetric titration –water determination based on volumetric measurement of reagent.

Good for high level moisture determinations.
�Coulometrictitration –water determination based on measurement of time and current (in
coulombs) used to generate the iodine. Good for low level moisture determinations.

Instrument Type Volumetric Coulometric

Best for Solids and Liquids Low moisture samples
Water content limit 50 ppm to 100% water 1 ppm to 100% water
Matrices Solid, Liquid and Gas Liquid only
Advantages All around performance Low detection limit

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(Two compartment system possess separate solvent and titrating solutions)

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5. Advantages:
A Karl Fischer moisture determination is advantageous, as compared to a
determination based on weight loss, because KF is not affected by volatile compounds. The
popularity of the Karl Fischer titration is due in large part to several practical advantages
that it holds over other methods of moisture determination, including:
i. High accuracy and precision
ii. Selectivity for water
iii. Small sample quantities required
iv. Easy sample preparation
v. Short analysis duration
vi. Nearly unlimited measuring range (1ppm to 100%)
vii. Suitability for analyzing: Solids, Liquids and Gases.
viii. Independence of presence of other volatiles
ix. Suitability for automation

In contrast, loss on drying will detect the loss of any volatile substance.

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6. Instrumentation:
Following Figure illustrates a simple dead-stop end-point assembly or a Karl Fischer
titration apparatus. The titration vessel is fitted with a pair of identical platinum electrodes,
a mechanical stirrer with adjustable speed, and a burette. It will be observed that absolutely
little or no current may flow unless and until the solution is totally free from any polarizing
substances; this could perhaps be due to the absorbed layers of oxygen and hydrogen on the
anode and cathode respectively.

However, the current shall flow only when the two electrodes get depolarized. The
Karl Fischer reagent is pumped into the burette by means of hand bellows, the access of
moisture is usually prevented by employing an appropriate arrangement of desiccant tubes.
Alternatively, the stirring may also be accomplished either by using a magnetic stirrer or by
means of suitably dried nitrogen passed gently through the solution during the course of
titration.
The end-point is achieved by employing an eiectrical circuit comprising of a
microammeter (A), platinum electrodes, together with a 1.5 V to 2.0 V battery connected
across a variable resistance of about 2.5 kΩ. First of all the resistance is adjusted in such a
manner that an initial current passes through the platinum electrodes in series with a
microammeter (A). After each addition of reagent, the pointer of the microammeter gets
deflected but quickly returns to its original position. At the end of the reaction a deflection
is obtained which persists for 10-15 seconds.
7. Water Determination Methodology:

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7.1 Volumetric titration method

Apparatus
Generally, the apparatus consists of an automatic burette, a backtitration flask, a stirrer, and
equipment for amperometric titration at constant voltage or potentiometric titration at
constant current.
Because water determination TS is extremely hygroscopic, the titration apparatus
should be protected from atmospheric moisture. Silica gel or calcium chloride for water
determination is usually used for moisture protection.
Procedure
As a rule, the titration of the sample with water determination TS should be performed at
the same temperature as that at the standardization of the TS, while protecting from
moisture.
The apparatus is equipped with a variable resistor in the circuit, and the resistor is
adjusted to apply a definite voltage (mV) between a pair of platinum electrodes immersed in
the solution to be titrated. The change in current ( �A) is measured during the dropping of
water determination TS (Amperometric titration at constant voltage). As titration continues,
the abrupt change in current in the circuit occurs, but returns to the original state within
several seconds. At the end of a titration, the change in current persists for a certain time
(usually, longer than 30 seconds). The end point of titration is determined at this electric
state.
Otherwise, by adjusting the resistor, a definite current is passed between the two
platinum electrodes, and the change in potential (mV) is measured during dropping water
determination TS (Potentiometric titration at constant current). With the progress of
titration, the value indicated by the potentiometer in the circuit decreases suddenly from a
polarization state of several hundreds (mV) to the nonpolarization state, but it returns to the
original state within several seconds. At the end of titration, the non-polarization state
persists for a certain time (usually, longer than 30 seconds). The end point of titration is
determined when this electric state attains.
In the case of back titration, when the amperometric titration method is used at
constant voltage, the needle of microammeter is out of scale while an excessive quantity of
water determination TS remains. It returns rapidly to the original position when the titration
reaches the end point.

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Similarly, when the Potentiometric titration method at constant current is used, the
needle of the millivoltmeter is at the original position while an excessive quantity of water
determination TS remains. A definite voltage is applied when the titration reaches the end
point. Unless otherwise specified, the titration of water with water determination TS is
performed by either of the methods below. Usually, the end point of the titration can be
observed more clearly in the back titration method than in the direct titration method.

7.1.1 Direct titration

Unless otherwise specified, proceed as directed below. Take 25ml of methanol for water
determination in a dried titration flask, and titrate with water determination TS to the end
point. Unless otherwise specified, weigh accurately a quantity of the sample containing 10
to 50 mg of water, transfer it quickly into the titration flask, and dissolve by stirring. Titrate
the solution with water determination TS to the end point under vigorous stirring. When the
sample is insoluble in the solvent, powder the sample quickly, weigh a suitable amount of
the sample accurately, and transfer it quickly into the titration vessel, stir the mixture for 30
minutes while protecting it from moisture.
Perform a titration under vigorous stirring. When the sample interferes with the Karl
Fisher reaction, water in the sample can be removed by heating and under a stream of
nitrogen gas, and introduced into the titration vessel by using a water-evaporation device.

7.1.2 Back titration

Unless otherwise specified, proceed as directed below. Take 20ml of methanol for water
determination in the dried titration vessel, and titrate with water determination TS. Weigh
accurately a suitable quantity of the sample containing 10 to 50 mg of water, transfer the
sample quickly into the titration vessel, add an excessive and definite volume of water
determination TS, stir for 30 min, protecting from atmospheric moisture, and then titrate the
solution with Water Methanol Standard Solution under vigorous stirring.

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Wheref = the number of mg of water (H2O) corresponding to 1 ml of water determination

TS,

Where,
f = the number of mg of water (H2O) corresponding to 1 ml of water determination TS,
f ’ = the number of mg of water (H2O) in 1 ml of Water Methanol Standard Solution.

7.1.3 General Remarks:

Volumetric Karl Fischer titration requires the determination of the titre (t) of the Karl
Fischer reagent. It is usually quoted in mg of water per ml of Karl Fischer reagent. Modern
reagents allow direct titration of water in the sample. The sample may be introduced
directly into the KF cell or after an extraction or dissolution with a suitable solvent. The
water concentration of the solvent must be determined previously in order to be subtracted
from the sample analysis. In Radiometer Analytical titrators all these operations are
simplified and the different results are accounted for automatically. The volumetric titration
of water allows the analysis of water concentrations between 0.1% and 100%. If an aliquot
contains less than 1 mg of water, coulometric determination will result in a more accurate
result. For reasons of precision, the titre of the titrant should be chosen so that the titration is
completed with a titrant demand between 1 and 10 ml
The working medium (i.e. the solvent required), can be freely chosen by the user
depending on the dissolution properties of the sample to be investigated. For methanol-
based reagents, the stoichiometry 1:1 of the Karl Fischer reaction is only fulfilled if there is
more than 25% methanol in the reaction mixture. A methanol-free working medium can be
used; however it is important to determine the titre of the KF reagent in the same working
medium. The modern solvents available today present a high buffer and dissolution
capacity. These solvents consist of sulphur dioxide, a base and methanol or ethanol. The
main advantages of these solvents are:
• A more rapid titration due to better reaction kinetics; an advantage especially for the
titration of large amounts of water.
• A better reproducibility, because the reaction environment is stable. The pH and the
sulphur dioxide concentration remain constant.

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For the titration of samples producing side reactions (aldehydes, ketones and
silanols), it is necessary to use an appropriate solvent. Most reagent manufacturers include
the letter K in the commercial name of such solvents.

7.2 Coulometric titration

Apparatus
Usually, the apparatus is comprised of an electrolytic cell for iodine production, a stirrer, a
titration flask, and a potentiometric titration system at constant current. The iodine
production device is composed of an anode and a cathode, separated by a diaphragm. The
anode is immersed in the anolyte solution for water determination and the cathode is
immersed in the catholyte solution for water determination. Both electrodes are usually
made of platinum-mesh.
Because water determination TS is extremely hygroscopic, the titration apparatus
should be protected from atmospheric moisture. For this purpose, silica gel or calcium
chloride for water determination is usually used. Procedure Take a suitable volume of an
anolyte for water determination in a titration vessel, immerse in this solution a pair of
platinum electrodes for potentiometric titration at constant current.
Then, immerse the iodide production system filled with a catholyte for water
determination in the anolyte solution. Switch on the electrolytic system and make the
content of the titration vessel anhydrous. Next, take an accurately weighed amount of the
sample containing 15 mg of water, add it quickly to the vessel, and dissolve by stirring.
Perform the titration to the end point under vigorous stirring. When the sample is insoluble
in the anolyte, powder it quickly, and add an accurately weighed amount of the sample to
the vessel. After stirring the mixture for 5 to 30 minutes, while protecting from atmospheric
moisture, perform the titration with vigorous stirring. Determine the quantity of electricity
(C) [electric current (A) and time (s)] required for the production of iodine during the
titration, and calculate the content (%) of the water in the sample by the formula.
When the sample interferes with the Karl Fisher reaction, water in the sample can be
removed by heating under a stream of nitrogen gas, and introduced into the titration vessel
by using a water-evaporation device.

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8. Interference and Limitations of Karl Fischer Method:

Interferences in the water determinations by Karl Fischer method are associated with
condensation or oxidation – reduction reactions with a number of substances and
compounds or by side reactions. Other possible interferences to the KF reagent are certain
active metals, metal oxides, metal hydroxides, chromates, melamines, etc.
The Karl Fischer titration has a number of serious limitations due to possible
interferences tantamount to erroneous results, namely:

(i) Oxidizing agents, for instance: chromates, Cu(II), Fe(III), Cr2O7 2–, peroxides, salts,
higher oxides,
Example: MnO2 + 4C5H5NH+ + 2I– → Mn2+ + 4C5H5N + I2 + H2O

(ii) Reducing agents, such as: Sn (II) salts, sulphides, and S2O32–, and

(iii) Compounds that have a tendency to form water with the ingredients of the Karl Fischer
reagent, for instance:
(a) Basic oxides: e.g., ZnO ;
Example: ZnO + 2C5H5NH+ → Zn2+ + C5H5N + H2O
(b) Salts of weak oxy-acids e.g., NaHCO3;
Example: NaHCO3 + C5H5NH+ → Na+ + H2O + CO2 + C5H5N
[Note: As H2CO3, carbonic acid, is very unstable; hence it splits up to yield a mole each of
water and CO2.]

Use of certain reagents will minimize or eliminate the interferences of many classes
of compounds. For example the use of non-methanol containing KF reagent and solvent will
reduce the interference from aldehyde and ketones. Ammonia and amines can be eliminated
by the addition of salicylic acid to the solvent.

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9. Side reactions:
Side Reactions are classified as:
(1) Reactions Influenced by Methanol
(2) Reactions with Iodine

(1) Reactions Influenced by Methanol

It includes:
• Aldehydes react to form acetals, also undergo Bisulfite addition

• Ketones react to form ketals

• Amines undergo methylation
• Siloxanes undergo esterification

(2) Reactions with Iodine

It includes:
• Halogenated Hydrocarbons containing free halogens
• Mercaptans (Thiols)
• Phenols
• Peroxides

Testing for Iodine Reactivity:

• Dissolve a few Iodine Crystals in Methanol and Introduce Sample
• Watch for Solution to Change Color, if Clear Iodine Reaction is Present

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1. Mercaptans (Thiols) are oxidized by iodine. Suppress this side reaction by treating
sample with N-ethylmaleimide in a buffered solvent system

2. Inhibition of Thiol Oxidation by Iodine

Most Phenols do not react with KF reagents, higher molecular weight phenols and
Amino-phenols are most problematic. Volumetric method is most suitable since the
Oxidation potential is high in coulometry or Acidify Solvent system to reduce interference

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10. Applications of Karl Fischer method for determination of Water in

pharmaceutical analysis:

10.1 PREDNISOLONE SODIUM PHOSPHATE

Materials Required: Karl Fischer Reagent*: 100 ml ; prednisolone sodium phosphate :
0.2gm; anhydrous methanol : 20.0 ml.

Procedure: Add about 20 ml of anhydrous methanol to the titration vessel and titrate to the
Amperometric End-point with the Karl Fischer reagent. Quickly add 0.2 g of prednisolone
sodium phosphate sample, stir for 1 minute and again titrate to the amperometric end-point
with the Karl Fischer reagent. The difference between the two titrations gives the volume
(v) of Karl Fischer reagent consumed by the sample.
The minimum water equivalent is 3.5 mg of water per ml of Karl Fischer reagent.
Hence, the percentage of water w/w in the given sample may be calculated by the
following:

Precautions:
(1) The reagents and solutions used must be kept anhydrous and necessary care should be
taken throughout to prevent exposure to atmospheric moisture,
(2) The Karl Fischer reagent should be protected from light and preferably stored in a bottle
fitted with an automatic burette, and
(3) The water equivalent of Karl Fischer reagent should always be determined before use.

10.2 COGNATE ASSAYS:

A number of other official pharmaceutical substances may be assayed for their water
content by the Karl Fischer method as summarized in the following Table:

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11. Automated Electrochemical Karl Fischer Analysis:

Commercially available Modern KF-Titrators are usually equipped with specifically
designed titration vessels that are exclusively meant to check and prevent the contact with
atmospheric moisture. Quite a few such devices are armed with microprocessors that will
perform the requisite operations sequentially in a programmed manner automatically; and
may also dish out a print-out of the desired results including the percentage moisture
content. In fact, these Modern KF-Titrators not only afford greater accuracy and precision
in results but also offer much ease and convenience in routine analysis as compared to the
classical techniques based on either caulometry or controlled current potentiometry using
two indicator electrodes.
Thus, the basis of the analysis rests upon the quantitative relationship existing
between charge passed and iodine produced by the reagent according to the above reaction.
Therefore, the generation of iodine is automatically stopped when an excess of it is detected
by the indicator electrode. It essentially consists of two platinum electrodes across which an
AC is applied and subsequently a marked drop in voltage between the electrodes takes place
as soon as an excess of iodine is present. Normally such automated instruments make use of
proprietory reagents exclusively.
The major advantage of this approach to KF-analysis being that no calibration is
required as the method is absolute and is entirely based on the stoichiometry of the
aforesaid equation. It is noteworthy that one may determine the amounts of water ranging
between 10 mcg and 10 mg in solid as well as liquid samples.

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12. Some of the innovative brands in Karl Fischer Auto – titrator

instruments:

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13. References:

1. Chapter 14, Karl fishcer method for determination of water, Page no. 223-227,
Pharmaceutical Drug Analysis, Ashutosh Kar, New age international limited publishers.

2. Aqua Stars, Karl fischer instruments, www.emdchemicals.com.

3. Karl Fischer Volumetric Titration Theory and Practice by Radiometer analytical

SAS, www.radiometer-analytical.com.

4. MettlerToledo AG, Analytical, Switzerland, www.mt.com.

5. Summary of Karl fischer titrations by Orion products, Baverly, MA, Thermofischer

Scientific, www.thermo.com/water.

6. Moisture determination by Karl Fischer titration: background of chemistry and

recent advances, Supelco/Sigma-Aldrich, Bellefonte, Pa, www.sigma-aldrich.com.

7. Karl Fischer Titration Methods. Methodology and water determination in 442

different substances, European Pharmacopoeia (Pharm.Europe), 4th Edition plus
Supplements 2002, International Electrotechnical Commission, Geneva.

8. Karl – fischer titration, www.wikipedia.com.

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