Drugs and Medicines – KF Volumetry, Japanese Pharmacopoeia – Suitability test | Karl Fischer titrator AQV-300/MOIVO-A19 - JM Science
HIRANUMA APPLICATION DATA Karl Fischer Titrator Data No. KF20 Apr. 13, 2022
Water contents Drugs and Medicines – KF Volumetry
Japanese Pharmacopoeia – Suitability test

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 of water per 1 mL of titrant. Factor is pre-determined before sample measurement and water content of sample is calculated from consumed titrant volume within sample measurement.

 In the method of “Water determination (Karl Fischer method)” in Japanese Pharmacopoeia Eighteenth Edition, the suitability test is described as a verification procedure when modifying the test procedures. In this report, a case example of suitability test is introduced with using glycerin as a simulated measurement sample.

Reference
1) Japanese Pharmacopoeia Eighteenth Edition

2. Apparatus and Reagents

(1) Apparatus    
  Titrator : HIRANUMA Karl Fischer Volumetric titrator AQV-series or MOIVO-A19
  Titration cell : Standard cell
  Sampler : Syringe
(2) Reagents    
  KF Titrant : AQUALYTE KF3 (HIRANUMA)
  An alternative if it is difficult to prepare, HYDRANAL Composit 5 (Honeywell)
  Titration solvent : HYDRANAL Methanol Dry (Honeywell)
(3) Sample    
    Measurement sample : Glycerin (Guaranteed reagent)
  Standard material : AQUALYTE Water Standard 10 (Assay: 10.01 mg/g, HIRANUMA)
  An alternative if it is difficult to prepare, HYDRANAL Water Standard 10 (Honeywell)

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. And then weigh it 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 as sample size.
(7) Repeat the measurement 3 times and obtain an average value for factor of KF titrant.
* The above sampling procedure is an example for a simulated sample. It should be performed according to the actual sample and the suitability test to be implemented.

Fig.3.1 Preparation of the titration solvent



Fig.3.2 Injection of sample

 

3.2. Procedure for suitability test

(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) Wash the syringe with the sample of glycerin and draw it into syringe. Then, weigh the syringe and record its read (Size 1 [g]).
(4) Inject the sample from rubber septum of titration cell as shown in Fig.3.2. The injection amount is adjusted so that the detected water (mg) is within 5 to 30 mgH2O.
(5) Start titration. Measurement parameter is shown in Table 4.2.
(6) Weigh the syringe again and record its read (Size 2 [g]). The difference of (Size 1-Size 2 [g]) is set as sample size.
(7) After measurement of the sample is finished, the device, setting parameters, and reagents are used without change, and the water standard is measured subsequently. Wash the syringe with the water standard and draw it into syringe. Then, weigh the syringe and record its read (Size 1 [g]).
(8) Inject the water standard from rubber septum of titration cell as shown in Fig.3.2. The injection amount is adjusted so that the detected water (mg) is 50 to 100 % of that of the sample measurement. Weigh the syringe again (Size 2 [g]). The difference of (Size 1-Size 2 [g]) is set as sample size.
(9) Repeat the measurement of the water standard 5 times.
* The above sampling procedure is an example for a simulated sample. It should be performed according to the actual procedure of the suitability test to be implemented with actual sample.

 

3.3 Analysis of suitability test result

(1) Prepare the value required for analysis from measurement result.
  M    :Determined water in the sample measurement result (mgH2O)
       ⇒ Initial water content determined for sample of glycerin (mgH2O)
  M1-x  :Amount of added water in the water standard measurement (mgH2O),
     “X” indicates the number of water standard measurement
       ⇒ Amount of added water (mgH2O)
  M2-x  :Amount of found water in the water standard measurement result (mgH2O),
     “X” indicates the number of water standard measurement
       ⇒ Amount of found water (mgH2O)
(2) Plot as follows using spreadsheet software.
 
(3) Create a regression line for the plots and find the following values.
  b : Slope of regression line
  a : y-axis intercept
  d : x-axis intercept
(4) The percentage errors e1 (%) and e2 (%) are calculated from the following formulae.
  e1 = {(a-M)/M} × 100
  e2 = {(|d|-M)/M} × 100
(5) From the following formula, calculate the water recovery rate r (%) for each of the 5 measurements of the water standard, and calculate the average water recovery rate R (%).
  r (%) = (M2-X/M1-X) × 100

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 sec
Max Volume 20 mL
Min Feed Vol. 0.01 mL
S.Timer 0 min
KF Buret No. 1  
     
     
     
     
Item    
KF Speed(OUT) 24 mL/min
KF Speed(IN) 24 mL/min
Back Ground ON  
Sample Size Input Every Time  
Blank Value 0 mL
E.P Detection uA  
Solvent S,O,CE  
C.P Level 150 uA
E.P Level 200 uA
Auto Interval 0 g
Auto Input OFF  

 

Table 4.2 Parameters for sample measurement

Item    
Cal Mode 0:Sample weight (net)  
Interval Time 30 sec
Max Volume 20 mL
Min Feed Vol. 0.01 mL
S.Timer 0 min
KF Factor 3.3917 mg/mL
KF Buret No. 1  
     
     
     
     
Item    
KF Speed(OUT) 24 mL/min
KF Speed(IN) 24 mL/min
Back Ground ON  
Sample Size Input Every Time  
Blank Value 0 mL
Unit Mode AUTO mL
E.P Detection uA  
Solvent S,O,CE  
C.P Level 150 uA
E.P Level 200 uA
Auto Interval 0 g

* The above parameter settings are examples for a simulated sample. They should be set according to the parameters for suitability test to be implemented with actual sample.

Table 4.3 Results of factor measurement of KF titrant

Sample Meas.
No.
Sample
size (g)
Titrant
volume (mL)
KF factor
(mg/mL)
Statistics result
Water 1 0.0269 7.92 3.3995 Avg. 3.3917 mg/mL
  2 0.0297 8.81 3.3735 SD 0.0158 mg/mL
  3 0.0321 9.44 3.4022 RSD 0.47 %

Fig.4.1 Measurement result of the sample



Fig.4.2 Example of measurement results of the water standard

 

Table 4.4 Values used for regression line of suitability test

Sample Meas.
No.
Sample
size (g)
Added water
M1-x
(mgH2O)
Found water
M2-x
(mgH2O)
x-axis
Cumulative added water
(mgH2O)
y-axis
M + Cumulative
found water
(mgH2O)
percentage
recovery
r(%)
Sample 1 7.1459 8.662
Water 1 0.6588 6.595 6.566 6.595 15.228 99.57
Standard 2 0.7001 7.008 6.994 13.603 22.222 99.80
  3 0.6728 6.735 6.651 20.337 28.873 98.76
  4 0.6680 6.687 6.624 27.024 35.497 99.06
  5 0.7204 7.211 7.136 34.235 42.633 98.96

Fig.4.3 Result of calculated regression line

 

Table 4.5 Result of suitability test for Japanese Pharmacopoeia

Item Result Standard Compliant
Found water of sample M (mgH2O) 8.662 5~30 mgH2O OK
Average percent recovery R (%) 99.23 97.5~102.5 % OK
y-axis intercept a (mgH2O) 8.715
Slope of regression line b 0.991 0.975~1.025 OK
x-axis intercept d (mgH2O) -8.794
Percentage error |e1| (%) 0.61 2.5 % or less OK
Percentage error |e2| (%) 1.52 2.5 % or less OK

5. Note

 According to the Japanese Pharmacopoeia Eighteenth Edition, the suitability test is implemented for the verification when the procedures of sample measurement are changed. Please check the latest version of Japanese Pharmacopoeia before conducting the suitability test.
 The condition parameters set in the device and the procedure of sample addition used in this report are examples for simulated samples. Adapt these to the actual sample to be verified by the suitability test.
Even if the sample, parameters, and sample addition method are different, the analysis procedure of suitability test can be performed in the same way.

 In addition, from the Eighteenth Edition of Japanese Pharmacopoeia, the suitability test was adopted and the specific description on the preparation of Karl Fischer reagent was deleted. The purpose of this is as follows; as premises for complying the suitability test, it is possible to select and use the appropriate KF reagent from commercially available products, considering the solubility and interfering reaction according to the properties of the measurement sample.


Keywords: Karl Fischer, Volumetric titration, Japanese Pharmacopeia, Suitability test
Hiranuma aquacounter aqv-300 volumetric karl fischer titratorHiranuma aquacounter volumetric karl fischer titrator moivo-a19Water contents

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