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Nonaqueous acid-base titrations – Common mistakes and how to avoid them

Nonaqueous acid-base titrations – Common mistakes and how to avoid them

Nonaqueous acid-base titrations are widely used in several industries, including the petrochemical  and pharmaceutical sectors. Whether you are determining the acid or base number (AN or BN) in oils or fats, titrating substances that are insoluble in water, or quantifying products with different strengths of acidity or alkalinity separately, nonaqueous acid-base titration is the method of choice.

If you already have some experience performing nonaqueous acid-base titrations, you may remember that there are several challenges to overcome in comparison to aqueous acid-base titrations.

In this blog post, I would like to cover some of the most typical issues that could pop up during nonaqueous acid-base titrations and discuss how to best avoid them. An important point to note is that there is no single solution regarding how to perform any nonaqueous acid-base titration correctly. The right procedure depends highly on the solvent and titrant used.

What is a nonaqueous acid-base titration?

Before discussing nonaqueous titrations, first let’s talk a little bit about aqueous acid-base titrations.

Here, a sample is dissolved in water, and depending of the nature of the sample (whether it is acidic or basic) a titration is performed either using aqueous base or aqueous acid as titrant. For indication, a glass pH electrode is used.

However, sometimes due to the nature of the sample, aqueous titration is not possible. Nonaqueous acid-base titration is used when:

  • the substance of interest is not soluble in water
  • samples are fats or oils
  • components of mixtures of acids or bases have to be determined separately by titration

In these cases, a suitable organic solvent is used to dissolve the sample instead of water. The solvent:

  • should dissolve the sample and not react with it
  • permits the determination of components in a mixture
  • if possible, should not be toxic

The solvents that are most often used include ethanol, methanol, isopropanol, toluene, and glacial acetic acid (or a mixture of these). Titrants are not prepared with water but rather in solvent. Frequently used nonaqueous basic titrants are potassium hydroxide in isopropyl alcohol or sodium hydroxide in ethanol, and a common nonaqueous acidic titrant is perchloric acid in glacial acetic acid.

Due to the nature of nonaqueous solvents, they are normally poor conductors and do not buffer well. This makes indication a bit challenging because the electrode must be suitable for such sample types. Therefore, Metrohm offers the Solvotrode which is developed specifically for nonaqueous titrations.

This pH electrode offers the following advantages over a standard pH electrode:

  • Large membrane surface and a small membrane resistance for accurate reading, also in poorly buffered solutions
  • A flexible ground-joint diaphragm which can easily be cleaned even when contaminated with oily or sticky samples, additionally it offers a symmetrical outflow for outstanding reproducibility
  • The electrode is shielded and is therefore less sensitive to electrostatic interferences
  • It can be used with any nonaqueous electrolyte such as lithium chloride in ethanol

In the following sections I will discuss the most common mistakes when performing potentiometric nonaqueous acid-base titrations and how you can avoid them.

Electrostatic effects

The influence of electrostatic effects during analysis is normally negligible. However, maybe you have once seen a curve like the one below which looks relatively normal until suddenly a spike occurs.

Figure 1. Titration curve with a spike which might have occurred from an electrostatic interference.

This is then an indication of an electrostatic effect. However, where does it come from and how can we overcome this?

Electrostatic charge can be generated from many sources, such as friction. For example, while walking across a surface you will generate an electrostatic charge which will be stored in your body. You have probably touched the doorknob after walking across a carpeted space in your socks and obtained a small electric shock—this is the discharge of built up electrostatic charge. If we now assume that you are electrostatically charged and then you approach an electrode that is currently measuring (in use), this will result in a spike (Figure 1). Therefore, it is essential to make sure that you are either properly discharged or that you do not approach the electrode during measurement. You can avoid this issue by wearing the appropriate clothes. ESD (electrostatic discharge) clothes and shoes are mostly recommended when performing nonaqueous titrations.

Blocked diaphragm

A blocked diaphragm is another point which occurs more regularly during nonaqueous titrations. Due to the oily and sticky sample, you might have seen that the electrode diaphragm is clogged and cannot be opened anymore. What should you do then?

In most cases, you can place the electrode in a beaker of warm water overnight. This treatment often helps to loosen the diaphragm. To completely prevent the diaphragm from clogging, a Solvotrode with easyClean technology should be used. With this electrode, electrolyte is released by pressing the head ensuring that the diaphragm is not blocked.

Choice of electrolyte and storage solution

We recommend two types of electrolyte for nonaqueous titrations.

For titrations with alkaline titrants: tetraethylammonium bromide c(TEABr) = 0.4 mol/L in ethylene glycol

For titrations with acidic titrants: lithium chloride c(LiCl) = 2 mol/L in ethanol

Please make sure to store the electrode in the same electrolyte with which it is filled.

Checking the electrode according to ASTM D664

To check whether the Solvotrode is still in good working condition, perform a test according to ASTM D664 using aqueous buffer solutions of pH 4 and 7. The procedure is as follows:

  • Measure the potential of buffer pH 4.0 while stirring and note the value after 1 minute
  • Remove the electrode and rinse it well with deionized water
  • Measure the potential of buffer pH 7.0 while stirring and note the value after 1 minute
  • Calculate the mV difference between the reading of buffers 4.0 and 7.0
  • The difference must be larger than 162 mV (20–25 °C) to indicate an electrode in good shape

If the measured potential difference is less than 162 mV, the electrode requires maintenance. Lift the flexible sleeve of the ground-joint diaphragm to let some electrolyte flow out. Repeat the measurement according to the steps above. If the value is still less than 162 mV, clean the electrode or replace it.

Proper rinsing and cleaning

Proper rinsing is essential if you want to obtain reliable results. Otherwise, the curve might flatten and the equivalence points are no longer recognizable. Figure 2 illustrates this phenomenon well.

Figure 2. Different determinations according to ASTM D664. With time, the start potential of the curves shifts which indicates an unsuitable cleaning procedure.

The sample is the same, however, you see that the equivalence point and starting potential begin to shift and the curves become flatter. This indicates an improper cleaning procedure between measurements. The corresponding electrode is shown in Figure 3.

Figure 3. Appearance of the electrode used in Figure 2 after five measurements.

This electrode was certainly not cleaned properly! Anyone who performs a nonaqueous titration must consider which solvent might best dissolve the residue—this is not an issue that other analysts can easily solve due to the nature of each individual sample. However, do not ignore an electrode with such an appearance.

Conditioning the glass membrane correctly

As you may remember from our previous blog post about pH measurement, it is essential that the hydration layer of the glass membrane stays intact. Nonaqueous solvents dehydrate the glass membrane rather quickly. A change in the hydration layer can have an impact on the measured potential, therefore it is important that the hydration layer is always in the same state before starting a titration to achieve the most reproducible results.

Proper electrode immersion depth

This can be established with a conditioning step of the glass membrane to rebuild the hydration layer. However, if the solvent is able to remove the hydration layer faster than it takes to perform a titration, this can lead to ghost equivalence points. Therefore, the electrode should be completely dehydrated and kept like this for all further titrations.


Polar solvents (e.g., ethanol, acetone, isopropyl alcohol, or mixtures with toluene)

Water-free solvents (e.g., dimethylformamide, acetonitrile, acetic anhydride, or mixtures of these)

Preparation of electrode

Store only the pH membrane (not the diaphragm) in deionized water overnight to build up a proper hydration layer.

Lift the flexible sleeve to allow some electrolyte to flow out.

Dehydrate the pH membrane by placing only the pH membrane (not the diaphragm) in the solvent you will use afterwards for titration.

Lift the flexible sleeve to allow some electrolyte to flow out.

Conditioning of glass membrane Place the pH membrane (bulb only) into deionized water for 1 minute. Place the pH membrane (bulb only) into the corresponding solvent for 1 minute.
Rinsing procedure Rinse electrode with 50–70% ethanol. If this does not help, use a suitable solvent to rinse the electrode and then clean afterwards with 50–70% ethanol. Rinse electrode with glacial acetic acid. If this does not help, use a suitable solvent to rinse the electrode and then clean afterwards with glacial acetic acid.
Remarks Make sure to always keep the bulb of the electrode in deionized water for the same time duration, otherwise the thickness of the hydrated layer (and therefore the response) may vary. Avoid any contact of the electrode with water as this can induce a reaction with the solvent causing ghost equivalence points and irreproducible results.

Maintenance of burets

It is not only the electrode that needs some special attention when performing nonaqueous titrations, but also the electrical buret. Some special maintenance is required since alkaline nonaqueous titrants are especially aggressive and they tend to crystallize, therefore leakage of the buret is likely.

The buret must be maintained on a regular basis according to the manufacturer’s instructions. Metrohm recommends the following procedure:

  • For shorter titration breaks, it is recommended to refill the cylinder with titrant (especially with OMNIS)
  • Clean the buret with deionized water at the end of the day
  • Lubricate the cylinder unit on the centering tube and on the cylinder disc

Also check the corresponding manual of the buret. The most important points are mentioned there which will lead to a longer working life of the buret.

Thermometric titration as an alternative

One alternative to using potentiometric nonaqueous acid-base titration is thermometric titration (TET), depending on the sample and analyte to be measured. Thermometric titration monitors the endothermic or exothermic reaction of a sample with the titrant using a very sensitive thermistor.

The benefit of TET over potentiometric titration is clearly the maintenance-free sensor which does not require any conditioning nor electrolyte refilling. More information about thermometric titration can be found in our previous blog posts below.


Hopefully this article has provided you with information about the main problems encountered during nonaqueous titrations. First, make sure that all electrostatic influences are eliminated. This will save a significant amount of troubleshooting. Then prepare and treat your electrode correctly before, during, and after titration. Make sure to condition the electrode right before your first measurement!

Of special importance here is the solvent you plan to use. If it is a polar solvent, the electrode should be conditioned in deionized water. If nonpolar solvents like acetic anhydride are used, the electrode should be dehydrated first. Between measurements, the electrode should be cleaned with a suitable solvent and the diaphragm should be opened on occasion.

Last but not least, take care of your buret. Maintain it regularly and replace it whenever necessary. With this advice, performing nonaqueous titrations should be a breeze!

For more information

about nonaqueous titrations, download our monograph:

Nonaqueous titration of acids and bases with potentiometric endpoint indication

Post written by Iris Kalkman (Product Specialist Titration at Metrohm International Headquarters, Herisau, Switzerland) and Dr. Sabrina Gschwind (Head of R&D at Metroglas, Affoltern, Switzerland).

Chemistry of Fireworks

Chemistry of Fireworks

Developed nearly two millennia ago in ancient China, fireworks are increasingly used in cultural celebrations around the world and enjoyed by nearly all ages. As one of the most entertaining forms of chemistry, fireworks appeal to our senses of sight and sound, offering a staggering variety of colors, sizes, shapes, sounds, and so on. We love to watch fireworks because they take our breath away with their magnificence and mystery.

However it is not all fun and games. The business of fireworks (and the field of pyrotechnics in general) is very serious since they should be made as safe as possible to use and also environmentally friendly. Beyond fireworks, other pyrotechnics are found in all kinds of entertainment, like in concerts, movies, and more serious applications for defense and security (e.g., safety measures like flares and signal lights).

What are fireworks made of?

Early fireworks were quite dangerous and were used for protection rather than for celebrations, and hardly resemble the ones we are now familiar with.

It all began back in Ancient China with the invention of gunpowder, which was created from a mixture of charcoal, sulfur, and saltpeter (potassium nitrate). Eventually, as new developments were made to increase the safety and predictability of using these early fireworks, experimentation with colors began and people started using them more for nonviolent purposes. Now there is an entire industry devoted to the development of all kinds of fireworks for consumers and professionals alike.

Learn more about the history of fireworks in the links below:

A firework, or aerial shell as it is also known, basically consists of three main parts aside from the housing: gunpowder and an igniter to make the rocket explode, and inside of the transported capsule on the top there are small garniture pods usually called «stars» (despite being shaped like spheres or cylinders) that include various chemicals for the desired effects. Stars consist of a colorant, a fuel, an oxidizer (oxygen providing substance, e.g., chlorates or nitrates), and a binder to hold the ingredient mixture together in a compact briquette.

The industry has spent a significant amount of time in development to make fireworks explode in shapes like stars and stripes, hearts, or even more complex forms like a cartoon figure, or letters and numbers if timed correctly.

Cross-sectional diagram of a firework capsule filled with star garnitures (72) and igniter (70). [1]

Forming a rainbow of colors

The vibrant colors of fireworks come from the combustion of metal ions which make up to 20% of the components. Metals have been used to color flames even before the invention of modern fireworks (e.g. Bengal fire). Chemically speaking, these metal ions change their electronic state by heating (addition of energy) and then going back to a lower energy state before emitting light of a certain color.

Table 1. List of metals used in pyrotechnics and their colors [2].



Example compounds


Strontium (intense red)

SrCO3 (strontium carbonate)

Lithium (medium red)

Li2CO3 (lithium carbonate)

LiCl (lithium chloride)



CaCl2 (calcium chloride)



NaNO3 (sodium nitrate)



BaCl2 (barium chloride)

B3N3 (boron nitride)


Copper halides

CuCl2 (copper chloride), at low temperature



CsNO3 (cesium nitrate)



KNO3 (potassium nitrate)

Rubidium (violet-red)

RbNO3 (rubidium nitrate)


Charcoal, iron, or carbon black



Titanium, aluminum, beryllium, or magnesium powders


Very prominent here is the yellow color from sodium which is also seen in older street lightbulbs in some countries. Unfortunately, the most vibrant colors formed are also the most toxic for the environment, like strontium (red) and barium (green). These contaminants can be measured in the air, water, and even in the soil—but more on that later.

Find out more information about how fireworks get their colors in the links below:

Safety first

Safety is always a critical issue when discussing fireworks, whether concerning their construction, their use, or their storage. Too many serious accidents have happened over the years involving fireworks.

Learn more about how to handle fireworks in a safe manner here:

Among one of the largest fireworks disasters recorded in Europe was in Enschede (The Netherlands) in 2000. This explosion occurred in the warehouse of the S.E. Fireworks factory, which was located in the center of a residential area as the city grew and continued to build homes around it. An entire neighborhood was razed and the largest of the explosions was felt up to 30 kilometers away.

Because of this incident, sales of larger fireworks in most European countries is only allowed outdoors. Accumulating fireworks at home in preparation for celebrations should be avoided at least in confined environments like basements or apartments. It is better to store them in a ventilated shed or car parking to avoid problems in the case of a fire. Also do not store fireworks for long periods, since most of commercial fireworks are meant to be used within 3–6 months after production because the paper contents can get humid, ionic substances can dissolve and recrystallize, and therefore the likelihood of a failure increases.

In the event of a firework failure: Never have a look immediately! Wait at least 15 minutes at a proper distance and then use a tool to confine it afterwards—never touch it with your bare hands, especially when dealing with exploding fireworks or rockets.

Having said this, fireworks have integrated some safety features over the last several years to work more properly and reliably. For instance, the propellants have been modified from containing black powder to using technology from rockets such as plasticizers for better burning performance during launch, also resulting in less smoke and dust on the ground. A dedicated chain of reactions has to be followed, otherwise it will burn in a harmless way.

Knowledge is power: Prevent accidents with proper analytical testing

In order to help prevent fireworks accidents such as the one in Enschede and countless others, it is crucial to closely monitor different quality parameters including the water content of paper-based fireworks, grain size of the metal particles, and the purity and composition of the colorant, just to mention a few. Adequate quality control provides an entertaining, but safe fireworks experience even in the hands of the general public, when proper protocols are followed.

Metrohm offers several analytical technologies and related applications for this area of research. Analyses can be performed for a wide variety of substances and quality parameters as well as trace materials in the laboratory, on the street, and in the air either via wet chemical methods (e.g., Karl Fischer titration, ion chromatography, voltammetry) or spectroscopic techniques (e.g., near-infrared spectroscopy [NIRS] and Raman spectroscopy).

As mentioned earlier, moisture is an important quality parameter when discussing the safety of explosive materials. Metrohm offers two different techniques for accurate analysis of water content in a variety of matrices which are outlined in the following blog posts.

When it comes to determining the individual concentrations of the main constituents, some wet chemical techniques really stand out. Suppressed anion chromatography is ideal for measuring the ionic components of e.g., firecracker powder, other explosive material, and even in explosion residues for forensic purposes. Coupling an ion chromatograph to a mass spectrometer (IC-MS) opens up even more analysis possibilities. Read more about these studies (and more) by downloading our free Application Notes.

The use of several different metal salts to create the vibrant colors of fireworks can be beautiful but also harmful to our health and that of our environment. Voltammetry (VA) is an electrochemical method suitable for the determination of trace and ultratrace concentrations of heavy metals and other electrochemically active substances. Not only is VA excellent at determining these substances in the laboratory, but also in the field such as for measuring the after effects of a fireworks display or an undesired event. Check out our selection of VA instruments and applications on our website.

Spectroscopic techniques like Raman can help to determine the presence of dangerous explosive materials even when keeping a safe distance by using different instrument attachments. Read our free White Paper about how to use MIRA DS from Metrohm Raman for the purpose of identifying explosives safely.

Environmentally friendly fireworks – a contradiction?

Although fireworks are a very spectacular form of entertainment, there is quite an environmental impact after big cultural events or national holidays. The general atmospheric pollution after a fireworks display has been set off can be seen in an increase of dust and smoke, but also heavy metal content in the air as most contemporary fireworks use these for coloring.

The unburnt material still contains a significant amount of heavy metals. After falling to the ground, this material can dissolve and enter the ground water after it rains. Plastics materials that covered the fireworks for safety reasons are found again as broken shell shrapnel or as microplastics. The combustion of the compounds inside the fireworks leads to increased air pollution in form of aerosols that can be measured and evaluated resulting in heavy metals in the air, fine dust, and even nanoparticles which are extremely harmful for our lungs.

Metrohm Process Analytics has developed the 2060 MARGA (Monitor for AeRosols and Gases in ambient Air) which is used by official agencies and research bodies worldwide to monitor the air quality fully autonomously. This instrument is based on the analytical technique of ion chromatography and can be used as a dedicated continuous air monitoring device that can be left unattended for several weeks at a time, or as a research instrument that can be used for other projects when not monitoring the air quality.

Learn more about the 2060 MARGA and its capabilities in our blog post.

To find out more about the use of Metrohm instruments to monitor the air quality, check out this selection of peer-reviewed articles.

A new «green» firework generation is being developed for both professional and indoor use to try to minimize the heavy metal content and also reduce aerosol forming agents. This makes them more suitable for indoor pyrotechnic shows and for movie production. In regular outdoor shows (e.g. at theme parks), the gunpowder for transport of the capsule has mostly been substituted with an air pressure gun mechanism.

A significant amount of research has gone into substituting heavy metal-based colorants with more environmentally benign substances by increasing the luminosity of lithium derivatives by substituting them for strontium, or by using boron instead of barium or chlorinated compounds.

Finally, the plastic parts commonly used to surround fireworks are planned to be substituted by microcrystalline cellulose mixtures with better plasticizing binders. This leads to a similar stability compared to the current plastic materials, but the cellulose-based containers burn up completely and do not leave harmful materials scattered on the ground.

The future of fireworks shows

All safety measures increase the joy of fireworks not only during, but also after the event—being green and being safe. Foretelling the future, some of these celebrations may now use a cadre of lighted drones in a choreographed dance. This has been happening more steadily as drones fall in price and increase in their handling and programming capabilities. However, fireworks have already been with us for a couple of thousand years, and probably will not disappear any time soon.

Download our free Application Notes

and White Papers related to explosives and propellants

Post written by Dr. Norbert Mayr (Ph.D. in the field of HEDM, pyrotechnics, propellants, and oxidizers), Marketing Specialist & Product Training at Metrohm International Headquarters, Herisau, Switzerland.

Validation of titration methods

Validation of titration methods

Manufacturing products of the highest quality is a must, especially in the pharmaceutical and food industries. This requires accurate, reproducible, and simple analysis methods that eliminate human errors as much as possible. Automated titration is one such solution that offers additional time and cost savings to laboratories.

After applying automation to a titration method, how can you ensure that the chosen method also delivers a reliable result? And how do you know that it is suitable for the analysis of your analyte(s)? This requires method validation of a titration, which includes standardization of the titrant as well as determination of accuracy and precision, linearity, and specificity.

USP General Chapter <1225> Validation of Compendial Procedures and ICH Guidance Q2(R1) Validation of Analytical Procedures: Text and Methodology define the validation elements – some of the most important ones are described in the following article.

These include (click to go to each section):


Dilution and weighing errors as well as the constant aging of all titrants lead to changes in the concentration of the titrant. To obtain results that are as reliable as possible, the most accurate titrant concentration is a prerequisite. Standardization of the titrant is therefore an integral part of a titration method validation. The standardization procedures for various titrants are described in the Volumetric Solution section of USP – NF as well as in the Metrohm Application Bulletin AB-206 regarding the titer determination in potentiometry.

The titrant to be used in the validation must first be standardized against a primary standard or a pre-standardized titrant. It is important that the standardization step and the sample titration are carried out at the same temperature.

Primary standards are characterized by the following properties:

  • high purity and stability
  • low hygroscopicity (to minimize weight changes)
  • high molecular weight (to minimize weighing errors)

The use of a standard substance (primary standard) allows accuracy to be assessed.

For more information about titrant standardization, check out our blog posts «What to consider when standardizing titrant» (for potentiometric titration) and «Titer determination in Karl Fischer titration».

Accuracy and precision

Accuracy is defined as the proximity of the result to the true value. Therefore, it provides information about the bias of a method under validation. Accuracy should be determined over the entire concentration range.

Precision is usually expressed as the standard deviation (SD) or relative standard deviation (RSD). It expresses how well the individual results agree within an analysis of a homogeneous sample. Here, it is important that not only the analysis itself but also all sample preparation steps are performed independently for each analysis.

Precision is evaluated in three levels:

  1. Repeatability: the precision achieved by a single analyst for the same sample in a short period of time using the same equipment for all determinations.
  2. Intermediate precision: analysis of the same sample on different days, by different analysts and with different equipment, if possible, within the same laboratory.
  3. Reproducibility: precision obtained by analyzing the same sample in different laboratories.

Determination of both accuracy and precision is necessary, as only the combination of both factors ensures correct results (Figure 1).

Figure 1. Only when both precision and accuracy are high can correct results be obtained, as high precision does not necessarily mean good accuracy, and vice versa.

For titration, accuracy and repeatability are usually determined together. At least two to three determinations at three different concentration levels (in total six to nine determinations) are recommended. For assays, the recommendation is to use a concentration range of 80% to 120% of the intended sample weight.


Linearity expresses whether a particular method gives the correct results over the concentration range of interest. Since titration is an absolute method, linearity can usually be determined directly by varying the sample size and thus the analyte concentration.

To determine the linearity of a titration method in the range of interest, titrate at least five different sample sizes and plot a linear regression of the sample volume against the titration volume consumed (Figure 2). The coefficient of determination (R2) is used to assess linearity. The recommendation is to use a concentration range of 80% to 120% of the intended sample weight.

Figure 2. Linear regression curve for the assay of potassium bicarbonate.


Impurities, excipients, or degradation products are among the many components that may be present in a sample. Specificity is the ability to evaluate the analyte without interference from these other components. Therefore, it is necessary to demonstrate that the analytical procedure is not affected by such compounds. This is the case when either the equivalence point (EP) found is not shifted by the added impurities or excipients, or in the event it is shifted that a second EP corresponding to these added components can be observed when a potentiometric sensor is used for indication.

Specificity may be achieved by using suitable solvents (e.g., non-aqueous titration instead of aqueous titration for acid-base titration) or titration at a suitable pH value (e.g., complexometric titration of calcium at pH 12, where magnesium precipitates as magnesium hydroxide).

How can this be implemented in practice? The titrimetric determination of potassium bicarbonate with hydrochloric acid will serve as an example here.

In this case, potassium carbonate is expected as an impurity with pkb values of 8.3 and 3.89. This makes it possible to separate the two species during the acid-base titration. Figure 3 shows the comparison of a curve overlay of the titration curves of potassium bicarbonate with and without added potassium carbonate.

Figure 3. Curve overlay of the specificity test using 1 g KHCO3 with and without 0.5 g K2CO3 (green and orange = no K2CO3 added; blue and yellow = K2CO3 added). Click to enlarge.

The lower titration curve corresponds to the solution containing both potassium bicarbonate and potassium carbonate. Two EPs are found here: the first EP can be assigned to the added potassium carbonate, while the second corresponds to the sum of potassium bicarbonate and potassium carbonate. The curve at the top of the figure clearly shows only one EP for the potassium bicarbonate solution without impurities.

Find out more about the proper recognition of endpoints (EP) in our previous blog post.


If you follow the recommendations above, you will be ready for titration method validation – and now it`s time to get started!

Using potentiometric autotitration instead of manual titration increases the accuracy and reliability of your results. In addition, the use of an autotitrator ensures that critical regulatory compliance requirements, such as data integrity are met.

Right from the start, Metrohm products provide peace of mind and confidence in the quality of the data you produce with proper IQ/OQ.

If you would like to learn more about Metrohm Analytical Instrument Qualification, have a look at our two blog posts dedicated to this important topic.

Additional security is also provided, e.g., by Metrohm Buret Calibration which ensures that the accuracy and precision of your dosing device are within the required tolerances. Traceable monitoring of the performance and function of the instrument through regular re-qualifications and tests is therefore a given.

Watch our free webinar

available on demand!

How to convert from manual to automated titration procedures

Post written by Doris Hoffmann, Product Manager Titration at Metrohm International Headquarters, Herisau, Switzerland.

The importance of titrations in pharmaceutical analysis

The importance of titrations in pharmaceutical analysis

If you are in the pharmaceutical industry and wonder if a conversion from a manual titration to an automated titration is suitable for your work, this blog post should give you all the answers you need.

I will cover the following topics in this article (click to go directly to the topic):

Applicability of modern titration methods in pharmaceutical analysis

Perhaps you have already heard or read about automated titration and its benefits in comparison to manual titration, but are now wondering whether those guidelines are also applicable to pharmaceutical analysis.

Getting straight to the point: Yes, it is true that many USP monographs as well as USP General Chapter <541> Titrimetry still refer to the manual visual endpoint titration. But there’s good news! USP-NF General Notices and Requirements Section 6.30 states:

As long as the alternative method is fully validated and you can prove that both methods are equivalent, you are allowed to use alternative methods.

Since titration still plays an important role in pharmaceutical analytical procedures and processes, Metrohm offers a variety of applications for innumerous API monographs of the United States Pharmacopeia as well as pharmacopeia-compliant analytical instruments.

Automated titration procedure

Have you wondered about how to perform the procedure of an automated titration—how does it differ from a manual titration? Working with a pharmacopeia compliant analytical instrument from Metrohm is not so different:


  1. Titrant is added with an automated 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.
Figure 1. Anatomy of an automatic titrator.

As shown in Figure 1, an automated titration procedure mainly consists of four steps. These steps are repeated until the end of the titration (Figure 2).

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

Figure 2. The titration cycle illustrating the different steps in an automated titration procedure.

If you are wondering how to transfer a manual titration to automated titration, then check out our earlier blog posts on this topic. Also, download our free white paper comparing manual and automated titration.

Choice of electrodes for pharmaceutical titrations

For autotitration, either an electrode or a photometric sensor is used to detect the point of a sample analyte neutralization. Metrohm offers a wide range of different electrodes for titrations that 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 brochure to learn more.

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

Maybe you are not quite sure which is the best electrode for your application. Therefore, Table 1 shows an interactive electrode guide for different pharmaceutical titrations.

Table 1. Electrode guide for pharmaceutical titrations.
Type of titration Electrode Close-up view Pharma Application / API

Aqueous acid/base titrations

e.g. titrant is NaOH or HCl

phenolphthalein indicator

Combined pH electrode with reference electrolyte c(KCl) = 3 mol/L

e.g. Ecotrode Plus, Unitrode

Water-soluble acidic and basic active pharmaceutical ingredients (API) and excipients

API: Benzbromaron, Potassium carbonate, Potassium bicarbonate

Non-aqueous acid/base titrations

e.g. solvent is organic or glacial acetic acid

crystal violet indicator

Combined pH electrode with alcoholic reference electrolyte LiCl in EtOH

e.g. Solvotrode easyClean

Water-insoluble weak acids and bases

Assay of API

Acid value (free fatty acids)

API: Caffeine, Ketoconazole

Redox titrations

e.g. titrant is sodium thiosulfate

starch indicator

Pt metal electrode

e.g. combined Pt ring electrode, Pt Titrode


Antibiotic assays

Peroxide value in fats and oils

API: Captropril, Paracetamol, Sulfonamide

Precipitation titrations

e.g. titrant is silver nitrate

ferric ammonium sulfate indicator

Ag metal electrode

e.g. combined Ag ring electrode, Ag Titrode

Chloride content in pharmaceutical products

Iodide in oral solutions

API: Dimenhydrinate

Complexometric titrations

e.g. titrant is EDTA

hydroxy naphthol blue indicator

Ion-selective electrode

e.g. combined calcium-selective electrode with polymer membrane

Calcium content in pharmaceutical products

API: Calcium succinate

Photometric titration

e.g. titrant is EDTA

Eriochrome black T indicator

Photometric sensor

e.g. Optrode

Assay of various metal salts in APIs

API: Chondroitin sulfate, Bismuth nitrate, Zinc sulfate

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

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.

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.


Metrohm is your qualified partner for all chemical and pharmaceutical analysis concerns and for analytical method validation.

In addition to full compliance with official directives, Metrohm instruments and applications comply with many of the quality control and product approval test methods cited in pharmacopoeias. Discover the solutions Metrohm offers the pharmaceutical industry (and you in particular!) for ensuring the quality and safety of your products.

Learn even more about the practical aspects of modern titration in our monograph and visit our Webinar Center for informative videos.

Need a reason to switch

from manual to automated titration?

How about FIVE?

Post written by Doris Hoffmann, Product Manager Titration at Metrohm International Headquarters, Herisau, Switzerland.

Recognition of endpoints (EP)

Recognition of endpoints (EP)

Like many of you, I gained my first practical titration experience during my chemistry studies in school. At this time, I learned how to perform a manual visual endpoint titration – and I can still remember exactly how I felt about it.

Using a manual buret filled with titrant, I added each drop individually to an Erlenmeyer flask that contained the sample solution (including the analyte to be measured) and the indicator which was added prior to the titration. With each drop and even slight color change of my sample solution, minutes passed with increasing uncertainty. I asked myself, «Have I already reached the true endpoint, should I add another drop, or have I even over-titrated?» You have probably been in the same situation yourself!

Sound familiar to you? Don’t forget to check out our other blog post about the main error sources in manual titration!

Several years have passed since then, and I am glad that I no longer have to face the challenges of performing a manual titration because Metrohm offers the possibility of automated titrations.

If you want to know how to determine the endpoint in an automated titration, I will give you all the answers you need. In the following article I will cover these topics (click to go directly to each):

    Different detection principles – an overview

    At this point you may ask yourself—if not visually, how the endpoint (EP) can be detected in an automated titration? Well, aside from the visual endpoint recognition (e.g., by a color change, the appearance of turbidity, or appearance of a precipitate), a titration EP can also be detected by the automated monitoring of a change in a chemical or physical property which occurs when the reaction is complete.

    As shown in the table below, there are many different detection principles:

    Table 1. Determination principles for various EP detection methods.

    Now, let’s discuss the potentiometric and photometric EP determination in comparison to a visually recognized EP detection as they are the most commonly used determination principles for automated titrations. If you’d like to learn more about the principles of thermometric titration, read our blog post about the basics!

    Potentiometric principle

    As shown in the table above, in the potentiometric principle the concentration dependent potential (mV) of a solution is measured against a reference potential. Therefore, a silver-silver chloride (Ag/AgCl) reference electrode is used in combination with a measuring electrode (pH sensitive glass membrane or metal ring). In general, a combined sensor (electrode) including both measuring and reference electrode is used.

    Figure 1 illustrates with a simple example how a manual titration with a color change looks when being converted to an automatic system.

    Figure 1. Illustration of the same titration performed manually (left) and automatically (right).

    Step 1: Beginning of the titration before titrant is added.

    Step 2: Addition of titrant – as the titration approaches the endpoint you begin to see signs of the color change. At this point in an automatic titration the sensor will detect a change in mV signal and the titrator begins dosing the titrant in smaller volumes and at a slower rate.

    Step 3: Finally, the EP is reached with a faint pink color which corresponds with the inflection point in the titration curve.

    Step 4: Titrating beyond the endpoint leads to over titration, and here the mV signal is fairly constant.

    This is how you achieve the characteristic S-shaped titration curve you see when performing an automated titration.

    Not only acid-base titrations can be converted. Figure 2 shows how a simple chloride titration can be converted. The titrant, titrant concentration, sample size, and sample preparation remain the same.

    Figure 2. Illustration of a chloride titration – conversion from manual to automatic analysis.

    Only the indicator is replaced by the Ag Titrode, a silver ring electrode, and we get a titration curve (Figure 2, right side) with a clearly defined endpoint.

    For more examples of possible potentiometric titrations, download our free monograph «Practical Titration» or check out our Application Finder where you can find several examples for all endpoint recognition principles.

    Photometric Principle

    Titrations using color indicators are still widely used e.g. in pharmacopeias. When performed manually, the results depend, quite literally, on the eye of the beholder. Photometric titration using the Optrode makes it possible to replace this subjective determination of the equivalence point with an objective process that is completely independent of the human eye.

    The advantage here is that the chemistry does not change – that is, the standard operating procedure (SOP) generally does not have to be adapted. 

    The basis of photometric indication is the change in intensity at a particular wavelength of a light beam passing through a solution. The transmission is the primary measured variable in photometry, and is given by the light transmission (mV or % transmission) of a colored or turbid solution that is measured with a photometric sensor such as the Optrode from Metrohm.

    There are eight possible wavelengths to choose from that span nearly all color indicators used for titrations (see table below). The shaft is solvent resistant and there is no maintenance required. It connects directly to the titrator and improves accuracy and repeatability of color indicated titrations.

    Table 2. The Optrode – an optical sensor for photometric titrations.

    I’ve also picked an example to show you how to convert an EDTA titration of manganese sulfate from manual titration to automated titration. Like in the example above, the procedure remains the same.

    Are you ready to take the leap and switch to using an automated titration system? Read our other blog post to learn more about how to transfer manual titration to autotitration.

    One advantage of automated titration is that a lower volume of chemicals is needed, resulting in less waste. With the same indicator Eriochrome Black TS, the Optrode is used at a wavelength of 610 nm. The titration curve (Figure 3, right side) shows a large potential change of the mV signal indicating a clearly defined titration endpoint.

    Figure 3. Illustration of the photometric EDTA titration of manganese sulfate according to USP.

    If you are not sure what the optimal wavelength for your titration is, then have a look at our blog post about photometric complexometric titration to learn more!

    Comparison: Optrode vs. potentiometric electrodes

    When you decide to make the switch to automated titration, there are some points to consider when comparing the Optrode with other Metrohm potentiometric electrodes. The following table lists the main criteria.

    Table 3. Comparison of photometric and potentiometric measurement techniques for a selection of factors.
    1Optrode has a working life of tens of thousands of hours.

    You see, an autotitration is quite simple to perform and has the great advantage that a clearly defined endpoint is given.

    Believe me, whenever I`m working with such a device including a suitable electrode for an automatic titration, I have a big smile on my face thinking back to my university days: Bye bye subjectivity, time-consuming procedure, economic inefficiency and non-traceability!

    Maybe you are now also convinced to make the change in your laboratory.

    Save more money

    with automated titration

    Read our blog post to find out more.

    Post written by Doris Hoffmann, Product Manager Titration at Metrohm International Headquarters, Herisau, Switzerland.