Quality Control of Pharmaceuticals using Titration Techniques

Quality Control of Pharmaceuticals using Titration Techniques


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  • Source: Metrohm India Private Limited

  • Date: 04 Jul,2022

With regard to the quality and safety of drugs, authorities worldwide set high standards for the pharmaceutical industry. These are documented in pharmacopoeias in the form of official collections of recognized pharmaceutical rules. As legal tools of consumer protection, they ensure that drugs are used safely. It is only the measuring and test procedures used within the framework of drug testing that identify a drug and determine whether it is approved or not. To ensure these high quality and safety standards, reliable instruments and methods are needed.

As a leading manufacturer of instruments for chemical analysis, and market leaders in Titration, we are aware of these challenges. For this reason, Metrohm offers you not only the latest instruments, but complete solutions for every titration application.

Metrohm is the competent contact for all matters concerning chemical-pharmaceutical analysis and the validation of analytical methods.

Apart from complying with numerous official guidelines, Metrohm instruments and applications satisfy the test methods for quality control and product release that are listed in the most important pharmacopoeias. Find the details in below table

Titration and Measurement Test methods referenced in USP-NF monographs

1.pH value

pH measurement is very critical in pharmaceutical samples, the Metrohm pH Module provides all that is needed for measuring the pH value according to USP<791>. With 900 Touch Control, or tiamoTM full, or Omnis Software, intelligent sensors, and five-point calibration it meets the requirements of FDA regulation 21 CFR Part 11.  Conductivity and pH value can be measured in the same vessel if the 856 Conductivity Module is combined with the 867 pH Module.

2.Conductivity Measurement

Particularly strict rules apply to the measurement of the conductivity of water for pharmaceutical use (water for injection) according to USP<645>. Apart from the highest level of precision, all the requirements of the U.S. FDA’s regulation 21 CFR Part 11 must be satisfied. The 856 Conductivity Module, together with the 900 Touch Control, or tiamoTM full, or Omnis software guarantees this.


Because of the simplicity and the accuracy of the procedure, a large proportion of the content determinations described in the monographs are carried out using titration methods, for example, according to USP<541>. Considering the latest methodological knowledge, Metrohm has developed hundreds of titration methods with Metro sensors based on the U.S. Pharmacopeia (USP) and European Pharmacopoeia (Ph.Eur.).

Some older USP methods are still frequently based on high sample weights, which require a titrant consumption of up to 50 mL.

Following Ph.Eur., Metrohm has reduced the sample weights considerably and thus cut titrant consumption to at most 10 mL.

All the methods have been worked out in such a way that you can adopt them as SOPs (Standard Operating Procedures) in your titration laboratory.

4.Water determination according to Karl Fischer

The quality, effectiveness, and shelf life of pharmaceutical products depends to a very large extent on their water content. For this reason, a great deal of importance is attached to water determination in pharmaceutical analysis. Thanks to the specific and selective reaction with water, Karl Fischer titration (KFT) is one of the most accurate and most reproducible water determination methods.

That is why, for many years, it has been prescribed in numerous pharmacopoeias as a standard method for fast and automatable water determination. If the test substance is completely soluble in the Karl Fischer reagent and does not enter into any secondary reactions with the solvent, the sample can be put directly into the titration cell and the water content determined directly using volumetry or coulometry.

Not all substances dissolve completely in methanol. This is, however, an important requirement for the correct determination of the sample`s water content. Some techniques for improving the solubility of samples are set out below. These techniques can also be combined with one another.

4a: Solubilizers

Depending on the test substance, solubilizers can be added. In the case of samples containing fat or oil, for example, ointments or creams, the KF reagent is treated with chloroform, to ensure that the sample dissolves completely.

4b: High-frequency homogenizers

Tablets must be ground to smaller particles prior to titration. This can be done either manually with a mortar or, more conveniently and above all more reproducibly, with the help of a high-frequency homogenizer directly in the closed titration cell. In this way one prevents the water content of the sample from changing during preparation.

In addition, in some cases, it is possible to dispense with the use of toxic solubilizers.

4c: Karl Fischer oven method

Many substances release their water only very slowly or only at high temperatures. Some react with KF reagents, forming water or consuming iodine, so the determined water content is incorrect. Such samples are unsuitable for direct Karl Fischer titration.

In the KF oven method, the test substance is heated in a tightly sealed vessel in an oven. The water-driven off from the sample is transported into the titration cell with the help of a stream of dry carrier gas; there it is determined, usually by means of coulometric Karl Fischer titration.

Because the sample itself remains in the vessel and only the water enters the titration cell, secondary reactions and matrix effects can be ruled out.

5: Automation: Increase your output without compromising on accuracy.

Metrohm offers automation solutions for measurement and titration applications. In automated processes, each sample is handled exactly the same way, and as a consequence, your results will be more consistent, and comparability will be improved.

The automation options allow you to perform homogenization, liquid handling, and analysis in one streamlined procedure.

With OMNIS Titration get Faster and more accurate titration results, you can perform up to four fully automated analyses at the same time. Compared to performing the same application on a stand-alone system, automation will save you up to 60% of the time. Using an OMNIS Sample Robot, you can profit from the automated changing of up to 175 samples. And once a rack has been analyzed, it can be replaced without stopping the analysis.

For more details visit us at: https://www.metrohm.com/en_in/products/titration/omnis-titration.html or write us at info@metrohm.in or WhatsApp us at +91-8925522992

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