HIRANUMA APPLICATION DATA

Watercontents

Karl Fischer Titrator

Data No.

KF11

Apr. 13,2022

Drugs and Medicines – KF Volumetry Back-Titration
Dextromethorphan Hydrobromide Monohydrate

1. Abstract
Water contents of drugs and medicines could be determined by Karl Fischer volumetric titrator. In
volumetric titration, the titrant have a factor which means the ability to react with how many milligrams ofwater per 1 mL of titrant. Factor is pre-determined before sample measurement and water content of sample iscalculated from consumed titrant volume within sample measurement.
There are two methods in KF volumetric titration, forward-titration and back-titration. Forward-titration isused in general. However, some of the sample should be measured by back-titration method according toPharmacopeias. In back-titration method, firstly excess amount of KF titrant is added to the water contained in
the sample, and then the remaining unreacted of KF titrant is titrated with water-in-methanol solution.
Therefore, it is necessary to measure the factor not only KF titrant but also the water-in-methanol before thesample measurement.
An example for water contents measurements of dextromethorphan hydrobromide monohydrate performedby back-titration method is introduced here. The measurement method was determined with the reference toJapanese Pharmacopeia. Please refer to Application Data No. 22 for the suitability test of JapanesePharmacopoeia eighteenth edition by the back titration method.
Reference
1) Japanese Pharmacopoeia Eighteenth Edition

2. Apparatus and Reagents(1) Apparatus
Titrator：

Karl Fischer Volumetric titrator

Additional Buret：1 unitTitration cell：Standard cell without drain valve

Sampler：

SyringeAQV-series

Powder funnel (Outer diameter of leg less than 12 mm)(2) ReagentsKF Titrant：

AQUALYTE KF3 (HIRANUMA)
An alternative if it is difficult to prepare
HYDRANAL Composit 5 (Honeywell)

Water-in-methanol solution
Titration solvent：

2 mg/mL, prepared from reagent grade methanol and DI water：

HYDRANAL Methanol Dry (Honeywell)(3) Sample
Dextromethorphan Hydrobromide Monohydrate (Guaranteed reagent)3. Procedure
3.1. Factor determination of KF titrant(1) Fill 50 mL of titration solvent into the titration cell as shown in Fig.3.1.
(2) Start blanking to attain stable background.
(3) Draw DI water into syringe. Then, weigh the syringe and record its read (Size 1 [g]).
(4) Inject a few drops of water from rubber septum of titration cell as shown in Fig.3.2. Approximate
amount of addition is 20-40 mg. (40-60 mg when using Composite 5 for KF titrant)(5) Start titration. Measurement parameter is shown in Table 4.1.
(6) Weigh the syringe again and record its read (Size 2 [g]). The difference of (Size 1-Size 2 [g]) is set assample size.
(7) Repeat the measurement 3 times and obtain an average value for factor of KF titrant.

Titration solvent

Fig.3.1 Preparation of the reagents

Note(1) Do not touch the tip of needle to titration
solvent.
(2) When injecting, set the tip of needle as
below figure.

(3) Before pulling out the needle, draw alittle air to prevent the sample fromadhering to the inside of rubber septum.

Fig.3.2 Injection of sample

3.2. Factor determination of water-in-methanol solution(1) Fill 50 mL of titration solvent into the titration cell as shown in Fig.3.1.
(2) Start blanking to attain stable background.
(3) Start titration. Measurement parameter is shown in Table 4.2.
10 mL of KF titrant is dispensed and then titrated by water-in-methanol solution.
(4) Repeat the measurement 3 times and obtain an average value for factor of water-in-methanol solution.
3.3. Sample measurement by back-titration(1) Fill 50 mL of titration solvent into the titration cell as shown in Fig.3.1.
(2) Start blanking to attain stable background.
(3) Put a sample container, powder funnel and spoon on the balance. Record its read (Size 1 [g]).
(4) Open the glass stopper of titration cell lid to introduce the sample with powder funnel as shown in
Fig.3.3.
(5) Start titration. First, 10 mL of KF titrant is dispensed into the cell and then titrated withwater-in-methanol solution. Measurement parameter is shown in Table 4.3. Set the factors measured in
section 3.1 and 3.2 for the KF reagent and the water-in-methanol solution.
(6) Weigh the sample container, powder funnel and spoon again and record its read (Size 2 [g]). The
difference of (Size 1-Size 2 [g]) is set as sample size.

Fig.3.3 Introduction of sample with powder funnel
3.4. Blank test measurement by forward-titration(1) Fill 50 mL of titration solvent into the titration cell as shown in Fig.3.1.
(2) Start blanking to attain stable background.
(3) Open the glass stopper of titration cell lid and introduce the funnel. Without adding the sample, leave
to stand for the same amount of time as it takes to add the sample in section 3.3, then attach thestopper.
(4) Start titration. Blank test is performed with forward-titration. Measurement parameter is shown in
Table 4.4.
(5) Set the result of titrant volume obtained in the blank test as the blank value for the measurement
conditions of the sample.

4. Parameters and results
Table 4.1 Parameters for factor measurement of KF titrant
Item
Cal Mode
7:KF Factor(By Pure water)
Interval Time
30 secMax Volume20 mL
Min Feed Vol.
0.01 mL
S.Timer0 min
KF Buret No.
1Item
KF Speed(OUT)
KF Speed(IN)Back GroundSample Size Input
Blank Value
E.P Detection
SolventC.P Level
E.P Level
Auto IntervalAuto Input

24 mL/min
24 mL/minOFF
Every Time
0 mLuA
S,O,CE
150 uA
200 uA0g
OFF

Table 4.2 Parameters for factor measurement of water-in-methanol solution
Item
Cal Mode
10:MeOH Factor(Back tit.MeOH)
Interval Time
30 secMax Volume
20 mL
Min Feed Vol.
0.01 mL
S.Timer0 min
KF Factor
2.9263 mg/mL
KF Buret No.
1
KF Disp.Vol.
10 mL
MeOH Buret No.
2
MeOH Disp.Vol.
10 mL
MeOH Timer
1 minItemKF Speed(OUT)
KF Speed(IN)
MeOH Speed(OUT)
MeOH Speed(IN)Back Ground
Blank Value
E.P Detection
C.P Level
E.P Level
Fact Meas.
Auto Input

24 mL/min
24 mL/min
24 mL/min
24 mL/min
OFF0 mLuA
150 uA
200 uA
1OFF

Table 4.3 Parameters for sample measurement by back-titration method
Item
Cal Mode
11:Back tit1(Fixed KFreagent disp)
Interval Time
30 secMax Volume
20 mL
Min Feed Vol.
0.01 mL
S.Timer
1 min
KF Factor
2.9263 mg/mL
KF Buret No.
1
KF Disp.Vol.
10 mL
KF Timer
1 min
MeOH Factor
2.0279 mg/mL
MeOH Buret No.
2MeOH Disp.Vol.
0 mL
MeOH Timer0 minItem
KF Speed(OUT)
24 mL/min
KF Speed(IN)24 mL/min
MeOH Speed(OUT)
24 mL/min
MeOH Speed(IN)24 mL/min
Back Ground
OFFSample Size Input Every TimeBlank Value
0.01 mL
Unit Mode
AUTO
E.P Detection
uA
C.P Level
150 uA
E.P Level
200 uA
Auto Interval0g

Table 4.4 Parameters for blank test by forward-titration method
Item
Cal Mode
13:Auto input blank value mode
Interval Time
30 secMax Volume
20 mL
Min Feed Vol.
0.01 mL
S.Timer
0 min

Item
KF Buret No.
KF Speed(OUT)
KF Speed(IN)Back GroundE.P Detection
C.P Level
E.P Level
Auto Input

124 mL/min
24 mL/min
OFFuA
150 uA
200 uAOFF

Table 4.5 Results of factor measurement of KF titrant
SampleWaterMeas.
No.
123Meas.
Time
0:04:25
0:04:09
0:03:28

SampleTitrant
KF factor
size (g) volume (mL) (mg/mL)
0.049016.74
2.9271 Avg.
0.052017.78
2.9246 SD
0.045415.51
2.9271 RSD

Statistic result
2.9263 mg/mL
0.0014 mg/mL
0.05 %

Table 4.6 Results of factor measurement of water-in-methanol solution
SampleKF titrant
10 mL

Meas.
No.
123

Meas.
Time
0:05:25
0:08:03
0:10:18

SampleTitrant
KF factor
size (g) volume (mL) (mg/mL)
014.442.0265 Avg.
014.442.0265 SD
014.412.0307 RSD

Statistic result
2.0279 mg/mL
0.0024 mg/mL
0.12 %

Table 4.7 Results of sample measurement
SampleBlank test
Dextromethorphan
Hydrobromide
Monohydrate

Meas.
No.
121
23

Meas.
Time
0:00:40
0:00:36
0:07:02
0:09:120:12:57

SampleTitrant
size (g) volume (mL)
0.01
0.01
0.20009.62
0.19689.64
0.1990
9.56

Water(mg)
9.725
9.685
9.847

Water
Statistic resultcontent (%)
Avg.
0.01 mL
4.8625Avg.
4.9106 %4.9212SD
0.0438 %4.9482RSD
0.89 %

5. Note(1) Sampling tools should be dried up well before use.
(2) Purge and fill the titrant homogeneously into the buret.
(3) Organic solvents which have relatively high volume expansion coefficient are used as a constituent oftitrant. For accurate measurement, factor titration and sample measurement should be performed at thesame room temperature as much as possible.
(4) When adding a solid sample to the cell by opening the stopper of the cell lid, blank test should be
performed separately to measure the water incorporated during the procedure of sample addition.
Perform the blank test by forward-titration method instead of back-titration, and set the obtained
titration volume in the blank value of the measurement condition of the sample.
(5) Compared to forward-titration, back-titration tends to take longer time to measure. If the titration
volume of the water-in-methanol solution can be predicted in advance, set a value 3 to 5 mL smaller
than the expected titration volume in the parameter "MeOH Disp. Vol.", and also set the parameter"MeOH Timer" to 1 minute. As a result, the measurement time is shortened by dispensing thewater-in-methanol solution with the set value immediately after the start of titration with thewater-in-methanol solution.
Keywords：Karl Fischer, Volumetric titration, Back titration, Pharmacopeia, Dextromethorphan hydrobromide

monohydrate