Drugs and Medicines – KF Volumetry, Back-Titration, Japanese Pharmacopoeia – Suitability test | Karl Fischer titrator AQV-300/MOIVO-A19 - JM Science
HIRANUMA APPLICATION DATA Karl Fischer Titrator Data No. KF22 Apr. 13, 2022
Water contents Drugs and Medicines – KF Volumetry Back-Titration
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.
 There are two methods in KF volumetric titration, forward-titration and back-titration. Forward-titration is used in general. However, some of the sample should be measured by back-titration method according to Pharmacopeias.
 In this report, the suitability test of Japanese Pharmacopoeia Eighteenth Edition was performed for dextromethorphan hydrobromide monohydrate, also introduced in Application Data No. 11, with back-titration method. Please refer to Application Data No. 11 for the factor determination of titrants procedure and the repeatability of measurement results for dextromethorphan hydrobromide monohydrate.

Reference
1) Japanese Pharmacopoeia Eighteenth Edition

2. Apparatus and Reagents

(1) Apparatus    
  Titrator : HIRANUMA Karl Fischer Volumetric titrator AQV-series or MOIVO-A19
  Additional Buret : 1 unit
  Titration cell : Standard cell without drain valve
  Sampler : Syringe
Powder funnel (Outer diameter of leg less than 12 mm)
(2) Reagents    
  KF Titrant : AQUALYTE KF3 (HIRANUMA)
  An alternative if it is difficult to prepare, HYDRANAL Composit 5 (Honeywell)
  Water-in-methanol
  solution
: 2 mg/mL, prepared from reagent grade methanol and DI water
  Titration solvent : HYDRANAL Methanol Dry (Honeywell)
(3) Sample    
  Measurement sample : Dextromethorphan Hydrobromide Monohydrate (Guaranteed reagent)
  Standard material : AQUALYTE Water Standard 10 (Assay: 10.06 mg/g, HIRANUMA)
  An alternative if it is difficult to prepare, HYDRANAL Water Standard 10 (Honeywell)

3. Procedure

3.1. Blank test measurement by forward-titration

(1) Fill 40 mL of titration solvent into the titration cell.
(2) Start blanking to attain stable background.
(3) Open the 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 3.2, then attach the stopper.
(4) Start blank test with forward-titration. Measurement parameter is shown in Table 4.1.
(5) Set the result of titrant volume obtained in the blank test as the blank value for the measurement conditions of the sample.

 

3.2. Procedure for suitability test

(1) Fill 40 mL of titration solvent into the titration cell.
(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.3.1. The addition amount is adjusted so that the detected water (mg) is within 5 to 30 mgH2O.
(5) Start titration. First, 10 mL of KF titrant is dispensed into the cell and then titrated with water-in-methanol solution. Measurement parameter is shown in Table 4.2. Set the factors determined preliminarily for the KF titrant 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.
(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) Open the glass stopper of titration cell lid to introduce the water standard. 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.


Fig.3.1 Introduction of sample with powder funnel

 

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 (mgH2O)
  M1-x  :Amount of added water in the water standard measurement (mgH2O),
     “X” indicates the number of water standard measurement
     Added amount of water standard (g) × Water assay of water standard (mgH2O/g)
       ⇒ Amount of water added (mgH2O)
  M2-x  :Amount of found water in the water standard measurement result (mgH2O),
     “X” indicates the number of water standard measurement
       ⇒ Amount of water found (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 blank test by forward-titration method

Item    
Cal Mode 13:Auto input blank value mode  
Interval Time 30 sec
Max Volume 20 mL
Min Feed Vol. 0.01 mL
S.Timer 0 min
     
     
     
Item    
KF Buret No. 1  
KF Speed(OUT) 24 mL/min
KF Speed(IN) 24 mL/min
Back Ground OFF  
E.P Detection uA  
C.P Level 150 uA
E.P Level 200 uA
Auto Input OFF  

 

Table 4.2 Parameters for sample measurement by back-titration method

Item    
Cal Mode 11:Back tit1(Fixed KFreagent disp)  
Interval Time 30 sec
Max 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. 2  
MeOH Disp.Vol. 0 mL
MeOH Timer 0 min
Item    
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 OFF  
Sample Size Input Every Time  
Blank Value 0.01 mL
Unit Mode AUTO mL
E.P Detection uA  
C.P Level 150 uA
E.P Level 200 uA
Auto Interval 0 g
     

Fig.4.1 Measurement result of the sample



Fig.4.2 Example of measurement results of the water standard

 

Table 4.3 Results of suitability test procedure

Sample Meas.
No.
Meas.
Time
Sample
size (g)
Titrant
volume (mL)
Water
(mg)
Water
content (%)
Statistics result
Blank test 1 0:00:40 0.01 Avg. 0.01 mL
  2 0:00:36 0.01    
Sample 1 0:07:33 0.2056 9.43 10.111 4.9178 * M = 10.111 mg
Water standard 1 0:10:54 0.7708 10.56 7.819 1.0144 Avg. 1.0135 %
  2 0:14:20 0.9248 9.82 9.320 1.0078 SD 0.0033 %
  3 0:17:54 0.8772 10.03 8.894 1.0139 RSD 0.32 %
  4 0:20:48 0.9600 9.61 9.746 1.0152    
  5 0:21:16 0.9512 9.65 9.665 1.0161    

 

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 0.2056 10.111
Water 1 0.7708 7.754 7.819 7.754 17.930 100.8
Standard 2 0.9248 9.303 9.320 17.058 27.250 100.2
  3 0.8772 8.825 8.894 25.882 36.144 100.8
  4 0.9600 9.658 9.746 35.540 45.890 100.9
  5 0.9512 9.569 9.665 45.109 55.555 101.0

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) 10.111 5~30 mgH2O OK
Average percent recovery R (%) 100.7 97.5~102.5 % OK
y-axis intercept a (mgH2O) 10.088
Slope of regression line b 1.008 0.975~1.025 OK
x-axis intercept d (mgH2O) -10.013
Percentage error |e1| (%) 0.2 2.5 % or less OK
Percentage error |e2| (%) 1.0 2.5 % or less OK

5. Note

A few things note for performing the suitability test

(1) In the suitability test, it is necessary to measure the water standard 5 times in succession without changing the titration solvent after measuring the sample. On the other hand, in back-titration, the KF titrant is dispensed and then titrated with water-in-methanol solution, so the increased amount of liquid in the cell per measurement is larger than forward-titration. The upper limit of the liquid volume in the standard cell is 150 mL. In this report, the titration solvent to be added to the cell at first was reduced to 40 mL so that the upper limit of the liquid volume was not exceeded during the suitability test.
In the standard cell, the minimum amount of titration solvent to add at first is 30 mL. If the liquid volume exceeds the upper limit of cell during suitability test, use an optional cell with a capacity of 200 mL (P/N: D327512-1 etc.).
   
(2) Since the water standard is a liquid, it is collected in a syringe and usually injected into the cell through a rubber septum. By injecting through a rubber septum, the liquid sample can be added without the outside air introduced to the cell during the injection.
In this report, since the sample of dextromethorphan hydrobromide monohydrate is a solid state, it requires to open the stopper of the cell for adding it. The method of adding the water standard in the suitability test is also performed in same procedure with the sample.

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

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