Water determination in pharmaceuticals using an automatedKarl Fischer Oven Technique
C. Dengler1, P. Kirschenbühler1, R. Schlink1, K.-H. Surborg2, Anette Junkersdorf2

Water release curve for metamizole sodium
The optimum oven temperature for driving off the water should ensure complete
water extraction in a reasonable time excluding decomposition of the sample. Thismeans that the oven temperature should be chosen as high as possible to ensure
short determination times, but still be 20 to 30 ˚C below the decompositiontemperature. The oven temperatures for unknown samples are determined on thebasis of the water-release curves that were recorded for all investigatedpharmaceuticals in the temperature range 50 to 250 ˚C.

Introduction
Quality and shelf life of active pharmaceutical ingredients depend primarily on thecontent of adsorbed (surface water) or bound water (water of crystallisation).
Although the 4th Edition of the European Pharmacopeia (2002) describes the direct
Karl Fischer (KF) Titration as the most important method for determining the watercontent, in some cases, where substances undergo side reactions with the KF
reagents or where they release their water only at high temperatures, theEuropean Pharmacopeia recommends the quantification via the loss on drying(LOD) in a drying cabinet or desiccator. However, besides the water to bedetermined, this method also includes all volatile compounds (e.g. impurities,degradation products) released at higher temperatures.
The KF Oven Method allows to resolve the above-mentioned problems. Dependingon the water content of the sample,
sample the KF titration can be performed either
volumetrically for higher or coulometrically for lower water contents. Considering
the relatively small amount of water in most pharmaceuticals, samples wereanalyzed coulometrically.

Instrumentation and Analytical Procedure 774 Oven Sample Processor
 756 KF Coulometer, including KF cellwithout diaphragm 728 Magnetic Stirrer
 6.5617.000 complementary equipment
for automatic reagent exchange and2.700.0020 Dosino (not shown) PC with VESUV 3.0 Metrodata softwarefor data acquisition, storage andreprocessing (not shown)
The calculation of the sample's water content involves also the determination ofthe humidity in the sample vessel and the moisture adhering to the vessel surface,vial cap and septum. Three empty but sealed sample vials are analyzed under theparticular sample.
p The resulting
g mean value is stored as asame conditions as the pblank value and automatically taken into account in the calculation.
Subsequently a threefold determination for each compound is performed.
Accuracy of the KF titrations is checked at regular intervals with a certified KF
Oven standard.

Titration curve for morphine hydrochloride
Karl Fischer

Summary
The Karl Fischer (KF) Oven Method permits the accurate, precise andstraightforward determination of the water content of pharmaceuticals that are
not amenable to direct KF titration because they either undergo detrimental side
reactions with the KF reagent or release their water only slowly or at hightemperatures.
Water determinations carried out with several pharmaceuticals demonstrate thatthe values obtained with the KF Oven Method all lie within the ranges specified in
the European Pharmacopoeia.
Pharmacopoeia Moreover,Moreover the automated KF Oven Techniquesignificantly enhances sample throughput and repeatability of the results.

By means of metamizole sodium,sodium a pharmaceutical that is not accessible to direct
KF titration, the determination of the adequate oven temperature is illustrated. The
red curve represents the absolute water released as a function of total time while
the blue curve corresponds to the associated drift as a function of oventemperature.

OCH3
N- +SO3Na
x H2O

N
N
H3C

The absolute amount of water and the drift are shown as a function of time.
 The three drift peaks point to the fact that morphine hydrochloride is present
in the form of its trihydrate.
 After 180 s no more water is released. The slight increase of the red curve
can be attributed to the background drift.

CH3Comparison KF Oven Method/LOD
Substance

Empirical formula

Water content

RecoveryCalcul Loss on KF Oven Method
Calcul.
dryingb(LOD)
RSDa[%][%][%][%]
Carbidopa

C10H14N2O4  H2O

Cysteinehydrochloride monohydrate C3H8ClNO2S  H2O

The water release curve was recorded using a heating rate of 2 ˚C/min.
 Both surface moisture and water of crystallisation are released within thefirst 1600 s (50…103 ˚C). Afterwards the drift (blue curve) drops to its originalvalue
l off approximately
i t l 10 μg/min/ i andd remains
i almost
lt constantt t forf 3800 s,increasing again at 5400 s.
 At 5400 s (230 ˚C) both curves indicate by their increase that water is released
by commencing decomposition→ For the rapid determination of the water content of metamizole
sodium a temperature of 150 ˚C assures a fast water release without
decomposition.

LOD
[%]

6.9-7.9

7.17

0.35

93.6-107.2

10.25 8.0-12.0

10.33

0.30

7.37

KFMelting Temp.
pointp774
Oven
[°C]

[°C]

97.3 203 - 205

150

78.0-117.1 100.8

 170c150

Ethacridine lactate monohydrate

C18H21N3O4  H2O

4.98

4.5-5.5

5.05

0.59

78.0-117.1 101.4

 180c180

Metamizole sodium

C13H16N3NaO4S  H2O

5.12

4.9-5.3

5.14

0.30

95.7-103.5 100.4 220 - 210c

150

Morphinehydrochloride

C17H20ClNO3  3H2O

14.37 12.0-15.0

13.83

0.44

83.5-104.4

 200c180

Quinine sulfate

C40H50N4O8S  2H2O

4.630.33

65.2-108.7 100.7 144 - 155

1354.6

3.0-5.096.2

a= mean value of threefold determination, b= given in the European Pharmacopoeia, c= melting with decomposition

In contrast to the wide range of the recovery rates for the loss on drying (LOD)
specified by the European Pharmacopoeia (60…120%), the KF oven method
provides recovery rates between 90 and 110% (examples cited in the tablebetween 96 and 101%). Additionally, the water content is determined with anexcellent repeatability in less than 12 minutes.

Advantages of the KF Oven Method
The Oven Sample Processor
 enables accurate and precise analysis of pharmaceuticals that formerly were
not amenable to KF titration
 avoids contamination of the oven and titration cell; consequently there are nocarryover and memory effects
 works nondestructively and requires only 15…30
15 30 mg of the potentiallyexpensive pharmaceutical allows recording of water release curves providing information about thekinetics of the water release

Download a copy of this poster from http://www.metrohm.com/com/Applications (search for 8.000.6078EN).

 significantly reduces manual sample preparation steps
 enhances sample throughput (high efficiency)
 analyzes all samples under identical und reproducible conditions, providing
results of the highest precision

1 Metrohm AG, CH-9101 Herisau/Switzerland, res@metrohm.com, phone +41 71 353 86 64
2 Pharmazeutisches Institut der Universität Bonn, D-53121 Bonn/Germany Phone +49 228 73 5212