Pharmacopoeial Aquametry (Karl Fisher Flashcards
What is the definition of aquametry?
An analytical process to measure the water present in a substance
Why is aquametry important?
If a pharmaceutical substance contains above the specified amount of water:
- Degradation by hydrolysis could increase
- Facilitates growth of microorganisms
- Increases weight of substance and therefore complicates calculations
Factors that can influence the hydration of a pharmaceutical product?
- Efflorescence
- Hygroscopy
- Deliquescence
- Exsiccation
Efflorescence
The loss of water of crystallisation to the atmosphere on exposure to air. If the vapour pressure of the hydrated substance is greater than the vapour pressure of the surrounding atmosphere, then the hydrated substance will lose water.
How can efflorescence be minimized?
Closing the container completely, and completely filling the container
What is meant by ‘hygroscopy’?
The ability of a substance to attract water molecules from the surrounding atmosphere
How does hygroscopy impact pharmaceutical products?
If a product attracts more water then the product can become physically changed, becoming more sticky, increasing in volume etc.
If a product attracts more water then the product can become physically changed, becoming more sticky, increasing in volume etc.
The material may absorb so much water from the atmosphere that it dissolves. This is known as deliquescence
What is meant by ‘exsiccation’?
The removal of water of crystallisation by heating. Heat is applied until a constant weight is achieved, or until the calculated weight loss has taken place
Why would we want to ‘exsiccate’?
Anhydrous substances may be required in formulation of certain pharmaceuticals. Exsiccation produces fine powders
How do we analyse and determine water content in pharmaceuticals?
- Drying
- Distillation
- Titration
What types of titration are used in determining water content?
- Acid-base titrations
- Redox titrations
How do the end points of titrations get detected?
By indicators, electrometrically or other methods such as pH change
By indicators, electrometrically or other methods such as pH change
the point in the titration when the exact stoichiometric amount of reagent has been added to react with the other reactant in solution
End point of a titration
What is actually measured. There is usually an unavoidable difference between the equivalence point and the end point
How does the Karl Fischer titration work?
The reaction proceeds in two stages:
- Alcohol reacts with SO2 and base to form a sulphite salt intermediate
- The sulphite salt reacts with iodine, which consumes water
How is water content determined from KF?
Iodine reacts with water in a 1:1 ratio, so if we know how much iodine was consumed then we know how much water was present
What are the two types of KF titration?
- Volumetric: Based on volume of KF reagent consumed
- Coulometric: Iodine is generated electrochemically at the anode of the titration cell. There is a direct relationship between total electric charge and the amount of iodine generated
What are the two types of volumetric KF titration?
- One component: Titrant contains all the components required for a KF reaction, such as iodine, sulfur dioxide, base and suitable alcohol solvent
- Two component: The titrant contains only methanol and iodine. The other KF components necessary are in the titration cell (better stability and faster, but more expensive)
What are the drawbacks to volumetric titration?
- KF reagents are quite unstable
- Titer must be determined over and over again to achieve accurate results
What are the benefits of volumetric titration?
- Preferred for samples containing large amounts of water
Coulometric KF titration
The required iodine is generated in situ by electrochemical means. Iodide is converted to iodine at the anode
What are the two main types of coulometric KF titration?
- Fritted cell
- Fritless cell
Fritted cell
Frit seperates the anode from the cathode, preventing iodine generated at the anode from being converted back to iodide at the cathode instead of reacting with water. Anolyte solution in anode chamber, smaller catholyte solution in cathode chamber
Fritless cell
No frit is present, bubbles generated by hydrogen act as a barrier that prevent iodine reaching the cathode. Uses same reagent at anode and cathode chamber
What are the methods of end point detection in KFT’s?
Visual detection, colorimetric detection, amperometric detection,
Visual detection
Visually seeing the colour change of KF reagent from brown to yellow. Not a good method as the colour change is not sharp
Colorimetric detection
Measuring absorbance at 525nm, the active reagent will absorb whereas the spent reagent will not. The absorbance will therefore remain close to zero until the end point is reached, wherein the excess iodine will cause an increase in the absorbance reading.
Better than visual, but still not great
Amperometric detection
- The preferred method
- Uses two platinum electrodes, where a constant voltage is applied to them and the current is measured
But how exactly does amperometric detection work?
- Current flows through the electrodes so long as iodine is present. This keeps the electrodes polarised
- When an excess of iodine is present, which occurs at the end point, the current will increase
- This current increase will cause the electrodes to depolarise and the titration stops completely
Other methods of measuring water content…
Loss on drying, distillation,
Loss on drying
- Used for measuring moisture in solid or semi-solid materials
- Uses diphosphorus pentoxide, which is a potent drying agent
- Weight of the sample is recorded before and after use of drying agent
- Weight loss taken as a percentage
Potential disadvantage of loss on drying technique?
Weight loss might not always be due to water removal
How to know which method is suitable?
Will be outlined in the British Pharmacopoeia
In general…KFT is suitable for…?
Determination of water content of a sample that is expected to be close to 100% water content, or 100ppm
Coulometric titration is suitable for…?
Determination of water content of a sample that is expected to be around 1ppm - 5%
Drawbacks of distillation?
Requires large samples and is therefore impractical in detecting trace amounts of water in pharmaceutical products
Loss on drying drawbacks?
Unsuitable for products containing other volatile substances - can cause weight loss from something aside from water loss
Drawbacks of titration?
Substances that can react with iodine or iodide can interfere with the result. Can also be quite expensive
Advantages of titration?
Rapid and specific for water, method can be fully validated and documented. Additionally, can be used for trace amounts of water
