Pharmacopoeial Aquametry (Karl Fisher

Question 1

What is the definition of aquametry?

Answer 1

An analytical process to measure the water present in a substance

Question 2

Why is aquametry important?

Answer 2

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

Question 3

Factors that can influence the hydration of a pharmaceutical product?

Answer 3

• Efflorescence
• Hygroscopy
• Deliquescence
• Exsiccation

Question 4

Efflorescence

Answer 4

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.

Question 5

How can efflorescence be minimized?

Answer 5

Closing the container completely, and completely filling the container

Question 6

What is meant by ‘hygroscopy’?

Answer 6

The ability of a substance to attract water molecules from the surrounding atmosphere

Question 7

How does hygroscopy impact pharmaceutical products?

Answer 7

If a product attracts more water then the product can become physically changed, becoming more sticky, increasing in volume etc.

Question 8

If a product attracts more water then the product can become physically changed, becoming more sticky, increasing in volume etc.

Answer 8

The material may absorb so much water from the atmosphere that it dissolves. This is known as deliquescence

Question 9

What is meant by ‘exsiccation’?

Answer 9

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

Question 10

Why would we want to ‘exsiccate’?

Answer 10

Anhydrous substances may be required in formulation of certain pharmaceuticals. Exsiccation produces fine powders

Question 11

How do we analyse and determine water content in pharmaceuticals?

Answer 11

• Drying
• Distillation
• Titration

Question 12

What types of titration are used in determining water content?

Answer 12

• Acid-base titrations
• Redox titrations

Question 13

How do the end points of titrations get detected?

Answer 13

By indicators, electrometrically or other methods such as pH change

Question 14

By indicators, electrometrically or other methods such as pH change

Answer 14

the point in the titration when the exact stoichiometric amount of reagent has been added to react with the other reactant in solution

Question 15

End point of a titration

Answer 15

What is actually measured. There is usually an unavoidable difference between the equivalence point and the end point

Question 16

How does the Karl Fischer titration work?

Answer 16

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

Question 17

How is water content determined from KF?

Answer 17

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

Question 18

What are the two types of KF titration?

Answer 18

• 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

Question 19

What are the two types of volumetric KF titration?

Answer 19

• 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)

Question 20

What are the drawbacks to volumetric titration?

Answer 20

• KF reagents are quite unstable
• Titer must be determined over and over again to achieve accurate results

Question 21

What are the benefits of volumetric titration?

Answer 21

• Preferred for samples containing large amounts of water

Question 22

Coulometric KF titration

Answer 22

The required iodine is generated in situ by electrochemical means. Iodide is converted to iodine at the anode

Question 23

What are the two main types of coulometric KF titration?

Answer 23

• Fritted cell
• Fritless cell

Question 24

Fritted cell

Answer 24

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

Question 25

Fritless cell

Answer 25

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

Question 26

What are the methods of end point detection in KFT’s?

Answer 26

Visual detection, colorimetric detection, amperometric detection,

Question 27

Visual detection

Answer 27

Visually seeing the colour change of KF reagent from brown to yellow. Not a good method as the colour change is not sharp

Question 28

Colorimetric detection

Answer 28

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

Question 29

Amperometric detection

Answer 29

• The preferred method
• Uses two platinum electrodes, where a constant voltage is applied to them and the current is measured

Question 30

But how exactly does amperometric detection work?

Answer 30

• 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

Question 31

Other methods of measuring water content…

Answer 31

Loss on drying, distillation,

Question 32

Loss on drying

Answer 32

• 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

Question 33

Potential disadvantage of loss on drying technique?

Answer 33

Weight loss might not always be due to water removal

Question 34

How to know which method is suitable?

Answer 34

Will be outlined in the British Pharmacopoeia

Question 35

In general…KFT is suitable for…?

Answer 35

Determination of water content of a sample that is expected to be close to 100% water content, or 100ppm

Question 36

Coulometric titration is suitable for…?

Answer 36

Determination of water content of a sample that is expected to be around 1ppm - 5%

Question 37

Drawbacks of distillation?

Answer 37

Requires large samples and is therefore impractical in detecting trace amounts of water in pharmaceutical products

Question 38

Loss on drying drawbacks?

Answer 38

Unsuitable for products containing other volatile substances - can cause weight loss from something aside from water loss

Question 39

Drawbacks of titration?

Answer 39

Substances that can react with iodine or iodide can interfere with the result. Can also be quite expensive

Question 40

Advantages of titration?

Answer 40

Rapid and specific for water, method can be fully validated and documented. Additionally, can be used for trace amounts of water