Quality control in the pharmaceutical industry is indispensable. As a selected test method, titration is described in many pharmacopeias due to its ease of performance and accuracy, as for example in the United States Pharmacopeia-National Formulary (USP-NF) General Chapter <541>. Here, potentiometric titration and other detection principles in an automated titration procedure exemplify a simplified approach compared to manual titration practices. This article details how to successfully switch from manual titration to automated titration in the pharmaceutical industry.

The following topics will be covered (click to jump directly to each):

• Applicability of modern titration methods in pharmaceutical analysis
• Automated titration procedure
• Choice of electrodes for pharmaceutical titrations
• Validation of titration methods
• Application examples

Applicability of modern titration methods in pharmaceutical analysis

General Chapter <541> Titrimetry describes the quantitative technique, focusing on the different types of titrations as well as the materials and equipment needed for the titration. The latest updated version of USP <541> now officially accepts automated titration as a modern titration method for pharmaceutical analysis. This General Chapter states that an automated titrator is a «multifunctional processing unit that is able to perform the steps of a titration» [1]. 

Compared to manual titration, automated potentiometric titration in pharmaceutical analysis improves on accuracy, precision, and efficiency. This is why Metrohm offers a variety of applications for several API monographs of the United States Pharmacopeia as well as pharmacopeia-compliant analytical instruments.

Learn more about the principles of titration in the blog post «Titration – definition and principles».

Automated titration procedure

Working with a pharmacopeia-compliant analytical instrument from Metrohm is quite easy. As shown in Figure 1, an automated titration procedure mainly consists of the following four steps.

1. Titrant is added with an automatic piston buret that safely controls the delivery of titrant to a precise level.
2. The sample is homogenized with a stirrer.
3. The electrode detects the titration endpoint, removing subjectivity of color changes.
4. Results are automatically calculated and displayed, allowing no room for human error.

These four steps are repeated until the end of the titration (Figure 2).

In addition, all devices that run with either our latest software OMNIS® or the previous software tiamo® are 21 CFR Part 11 compliant meeting all ALCOA+ requirements. Thanks to the improvements in productivity, accuracy, and precision, any human influence on the analysis is reduced to a minimum. 

For more information, read our brochure on the OMNIS Compliance Package of Metrohm instruments.

If you are wondering how to transfer a manual titration to automated titration, then check out our other blog post on this topic. Also, download our free White Paper comparing manual and automated titration.
 

Blog post: How to Transfer Manual Titration to Autotitration

White Paper: Manual vs. Automated Titration: Benefits and Advantages to Switching

Choice of electrodes for pharmaceutical titrations

Metrohm has a vast portfolio of different electrodes for titrations. Whereas separate electrodes were used in the past, we now offer many space-saving, convenient, and user-friendly combined electrodes. These combined electrodes contain the reference electrode (usually a silver/silver chloride electrode) and an ion-selective glass electrode that serves as an indicator electrode. For autotitration, photometric sensors can be used in addition to the established electrodes. Both types can detect the point of a sample analyte neutralization and are extremely suitable for various pharmaceutical applications. 
 

The electrode choice depends on the type of reaction, the sample, and the titrant used. Download our free flyer here to learn more.

Electrodes for titrations - Which electrode for which application?
 

If you want to know more about how endpoints are recognized using electrodes or photometric sensors, read our related blog post to find out how the endpoint is determined during an autotitration.

Recognition of endpoints (EP)
 

Maybe you are unsure regarding which electrode is the best for your application. Therefore, the following subsections give an interactive electrode overview for various pharmaceutical titrations.

To help you select the best electrode for your titrations, we have prepared a flyer for you to easily find the perfect electrode for USP monographs. Additionally, you will find information about proper sensor maintenance and storage.

Flyer: Electrodes for USP monographs

If you prefer, the Metrohm Electrode Finder is even easier to use. Select the reaction type and application area of your titration, and we will present you with the best solution.

Try out the Metrohm Electrode Finder

As documentation and traceability are critical for the pharmaceutical industry, Metrohm has developed fully digital electrodes, called «dTrodes». These dTrodes automatically store important sensor data, such as article number and serial number, calibration data and history, working life, and the calibration validity period on an integrated memory chip.

Check out dTrodes for OMNIS here!

We also prepared a troubleshooting blog post to help identify possible causes of issues and show you how to avoid or fix them.

Blog post: Best practice for electrodes in titration

Validation of titration methods

In the pharmaceutical industry, the validation of analytical methods is an important quality assurance tool. The suitability and applicability of a selected method for an intended analytical purpose can only be proven by means of validation. The many applications offered by Metrohm show that, in addition to the regulatory guidelines, titration methods also comply with the test methods specified in the pharmacopeias. Our blog article «Validation of titration methods» deals with the most important aspects of method validation in accordance with USP General Chapter <1225>. 

It is not only Metrohm applications that are in accordance with the pharmacopoeias. Metrohm instruments also comply with many of the quality control and product approval test methods cited therein. For more information about analytical instrument qualification, check out our blog series.

Blog post: Introduction to Analytical Instrument Qualification – Part 1

Blog post: Introduction to Analytical Instrument Qualification – Part 2

Application Notes

In this section, we present a curated selection of Application Notes on titration methods in pharmaceutical analysis. If you cannot find the information you are looking for, please contact a Metrohm representative for further assistance.

Conclusion

In the current <Titrimetry> General Chapter from the USP, titration is no longer required to be carried out manually. Using a suitable sensor, the equivalence point can also be determined by means of automatic titration. In contrast to visual detection, physical detection has many advantages like better accuracy and precision, not to mention the time savings. 

Metrohm instruments and applications are in accordance with many of the quality control and product approval test methods cited in pharmacopeias. This confirms once again that Metrohm is the right and qualified partner for all chemical and pharmaceutical analysis concerns and for analytical method validation.

Reference

[1] <541> Titrimetry; U.S. Pharmacopeia/National Formulary: Rockville, MD. DOI:10.31003/USPNF_M99300_01_01

Your knowledge take-aways

Metrohm Webinar Center: Titration

White Paper: Manual vs. Automated Titration: Benefits and Advantages to Switching

Monograph: Practical aspects of modern titration