Introduction
In the quality control department Instrument section is an essential part because every test requires a specific instrument to perform a valid analysis. Karl Fischer titration is very essential in many analyses including finding the water content in any substance. Most of the APIs used in the pharmaceutical Industry have water content in their compound, it is very essential to know the exact value of water in the compound before using the API for formulation. Therefore, Karl Fischer titration is a very important test in the laboratory. The calibration of Karl Fischer is equally important to get the right analysis values.
Principle of Karl Fischer titration
The main principle of Karl Fischer titration is based on Bunsen’s reaction between Iodine solution and sulfur dioxide in an aqueous base solution. Later on, Karl Fischer modified the reaction in a non-aqueous base medium to find the water content as neutralizing sulfur dioxide by titration. The reaction consumes water (H₂O) in a 1:1 ratio according to the equation : H₂O + SO₂ + I₂ → SO₃ + 2HI
The endpoint of the titration is reached when the whole water content in the sample is neutralized, and iodine appears excess in the solution. For knowing the excess amount of iodine various methods can be used.
- In volumetric Karl Fischer titration, a solution with a known concentration of iodine is added until the endpoint, and the water content is determined based on the volume of the added solution.
- On the other hand, In coulometric Karl Fischer titration, iodine is electrochemically generated till the endpoint is reached, in this process the water content is determined by the amount of electricity used for this generation
Karl Fischer titration and calibration Procedure:-
General Precautions to follow:-
(1) The glassware to be used should be well-dried and cleaned.
(2) Never drop the magnetic rotor into the beaker but slide it inside carefully.
(3) Adjust the height of the electrode such that the platinum tips are at least 15 mm above from the bottom of the beaker to avoid damage during stirring.
(4) Apply sufficient vacuum grease to all ground glass joints.
(5) Do not start the instrument unless the inlet and outlet tubes are connected properly to avoid spoilage of the reagent.
(6) Clean the instrument immediately to avoid corrosion due to reagent spoilage.
(7) Close the bottle tightly immediately after use to avoid exposure to atmospheric moisture.
Calibration Operation:
(i) Calibrate with distilled water.
(ii) Add about 250 ml of KF reagent in the back fitted left-hand side reservoir bottle.
(iii) Remove the rubber cork and add KF-grade methanol to the reaction beaker in the quantity that shall suffice for fully immersing the platinum tip. Place the rubber cork immediately.
(iv) Connect the Titrator to the mains supply and put the main switch ON and also On from the backside button. Adjust the speed of the stirrer at minimum.
(v) Press the ‘Start’ key to start the Neutralization of moisture in methanol.
(vi) During titration display shall show the Confirmation time of 20 sec and also show the consumption of KF reagent in ml.
(vii) After Neutralization completion a long beep shall sound and display automatically show consume the volume of the KF reagent.
Step by Step guide to calibrating the manual Karl Fischer titrator:
- Prepare the fresh KF reagent as per the SOP for reagent preparation and the manufacturer’s manual.
- Weigh the standard Sodium Tartrate Dihydrate accurately, the standard should be certified, and the weight in the notebook.
- Titration Setup for analysis: Fill the titration cell of the titrator with fresh prepared KF reagent and install the electrodes carefully.
- Run a blank titration without putting standard to titration cell, it will help to determine the background signal or drift.
- Now, add the weighed standard into the titration cell, and titrate until the endpoint is obtained, Record the volume of the KF reagent consumed.
- Then calculate the titer of the KF reagent using the standard’s weight and the volume of the KF reagent consumed in the titration.
- Also, calculate the drift correction factor using the blank titration results found before starting the standard’s titration.
- Adjust the titer of the KF reagent by multiplying it with the drift correction factor.
- Now, verify the titer adjustment by performing another titration with the same standard. The results should be within the acceptable limit of deviation.
- Record all the calibration data, including the date, the standard used, the volume of KF reagent consumed, the titer, the drift correction factor, and the adjusted titer in the calibration logbook or sheets, do signatures of the test performer chemist, and the Quality Manager who approved the calibration process.
For Solid samples or Raw materials:
(i) Accurately weigh the sample on the balance & press the ‘sample (gm-ml)’ key & ‘enter’ the weight that is taken.
(ii) Transfer the weight to the reservoir bottle and then press “Start” to measure Moisture Content in the sample.
(iii) After Completion of Titration a long beep shall sound and display automatically show the consumed volume of KF reagent.
(iv) Accurately take the volume of the sample by using a calibrated syringe & press “density”
(v) Key & ‘enter’ the volume and density of the sample that was taken.
(vi) Transfer the volume to the reservoir bottle and then press “Start” to measure Moisture Content in the sample.
(vii) After Completion of Titration, a long beep is sounded, and the display automatically shows the consumed volume of the KF reagent.
(viii) Press% PPM key to show the Moisture Content in the sample it will show the moisture in
“Percentage”, “PPM” and “mg of H2O”.
(ix) Press the “batch No.” key to put the batch no. of the sample.
(x) Note down the result and take a printout (If required).
Diagram of Karl Fischer Titrator
Calibration:
The instrument Calibrates itself prior to all tests. (Fully Automatic)
List of annexures and formats.
S. No.
Format Title
Annexure Number
Format Number
No. of Pages
1. Usage logbook 2.Monthly Calibration record 3. Daily calibration record 4. Calibration status label
The user manual of Karl Fischer
Safety Precautions
(1) Ensure that the titration vessel is completely dry and clean at the start of the analysis.
(2) The titration vessel is airtight during titration.
(3) Silica gel should be blue and dry.
(4) Ensure that electrode tips are properly dipped in methanol.
Frequency: once a day (KF Factor) and monthly (Equipment Calibration)
Top 3 Karl Fischer Titrator used in Pharma Industry Labs.
- Lab Junction Karl Fischer Moisture Titrator, Microprocessor Karl Fischer Moisture Titrator-BUY
- Labgo Auto Karl Fischer 002; See here
- VSI ELECTRONICS PRIVATE LIMITED VSI-71 Microprocessor Karl Fischer Moisture Titrator; Learn more
The Instrument Karl Fischer Titrator is necessary for the pharmaceutical industry for several reasons:
- Many pharmaceutical products and APIs contain water content in their molecules, which can affect the stability of products, efficacy, and also shelf-life. To rule out such issues determination of water content in products and API used in the manufacturing of products is carried out. After knowing the exact value of water several factors can be applied to the requisition of Raw materials to overcome the loss of water content during the process and life duration.
- Karl Fischer titrator is an essential instrument in the Laboratory according to FDA regulations. It is equally important as UV Visible Spectrophotometer, and HPLC in the laboratory of any manufacturing company.
- Karl Fischer’s titrator is also important for process optimization in the company. It can help a manufacturing chemist to calculate the possible loss of mass during the manufacturing process by knowing the actual water content in the API used.
Summary
Karl Fischer titration and Calibration demand high precision during performing the titration. Determination of water content may vary if the weight of the material differs in mg. Every aspect of analysis should be performed very carefully and should be noted down immediately to rule out any errors. These days automatic Karl Fischer titrators minimize the chances of manual errors but still precision is required to get the best results. Karl Fischer’s titrator is a great invention for the analytical world.
References
- Water Determination<921>-USP-31
- GR Scientific, 71-0000, Aquamax Coulometric Karl Fischer Titrator-Buy Amazon
- Karl Fischer Titration: Determination of Water by Volhard Method, by E. W. Schmid, ISBN 978-3-527-60936-9.-pdf
- Karl Fischer Titration: A Practical Approach, by G. G. Guilbault, ISBN 978-0-8247-9753-3.
- Metrological Aspects of Karl Fischer Titration, by J. M. Llabrés i Xamena, Journal of Chemical Education, Vol. 77, No. 11, 2000, pp. 1475-1479.
- Karl Fischer Titration: Recent Developments and Applications, by J. P. Hartmann and K. D. Luong, Analytical Chemistry, Vol. 65, No. 12, 1993, pp. 707A-712A.
- Calibration of Karl Fischer Titrators: A Review, by G. G. Guilbault, Analytica Chimica Acta, Vol. 288, No. 2, 1994, pp. 173-181.
- The Use of Gravimetric Standards for the Calibration of Karl Fischer Titrators, by J. M. Llabrés i Xamena, Journal of Chemical Education, Vol. 84, No. 2, 2007, pp. 325-327.
- Development of a New Calibration Method for Karl Fischer Titrators, by Y. Zhang, Q. Wang, and X. Zhang, Analytical Letters, Vol. 53, No. 14, 2020, pp. 2266-2278.
- Calibration and Validation of Karl Fischer Titrators: A Comparison of Different Approaches, by M. T. P. Silva, P. E. P. Ferreira, and J. L. F. C. Lima, Analytical Sciences, Vol. 29, No. 9, 2013, pp. 899-904.
- A Comparison of Different Calibration Methods for Karl Fischer Titrators, by M. A. G. Zeeshan, A. Akbar, and S. G. Khan, Journal of Chemical Engineering Data, Vol. 63, No. 9, 2018, pp. 3337-3342.
- Standard Test Method for Determination of Water in Petroleum Products, Lubricating Oils, and Additives by Coulometric Karl Fischer Titration, ASTM D6304-16, ASTM International, West Conshohocken, PA, 2016, www.astm.org.
- Principles of Karl Fischer Moisture Measurement-Hiranuma(website).
Video: Karl Fischer titration for moisture content determination in food and pharmaceutical products: By Dr. Usha Rani
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