Manual Titration to Automated Titration | USP Recommendations

While several titration methods for assays in compendial monographs are being converted to chromatographic methods or other quantitative procedures, titration still plays an important role in pharmaceutical analytical procedures and processes. Several applications, such as distinguishing between carbonate and bicarbonate or monobasic and dibasic phosphate salts, are only feasible by titration, making titration a fit for purpose method.

For example, water determination by Karl Fischer (KF) titration is highly selective for water and sensitive enough to reach to the ppm level.

While the industry is already utilizing modern KF titration instruments for selective and reliable water content determination, many USP monographs still refer to the manual visual end point titration methods for other applications.

Visual indication with color indicators is the oldest method of determining the equivalence point of a titration, and it is still frequently used and proposed in different guidance documents. It is inexpensive and requires few pieces of equipment.

However, it can be tedious to determine the endpoint by adding a titrant dropwise with a manual buret until the color change is stable. A further drawback of the method with visual indication is that the color perception of individual operators differs and can depend on the lighting conditions.

Furthermore, visual endpoint detection is hampered in colored and/or turbid solutions. These factors reduce the reliability of the results as they become more prone to human error.

An even bigger drawback is that the visual method cannot be automated and is therefore difficult to validate and it lacks data integrity.

Conversion of a manual titration method to a semi-automated or automated titration method can be achieved successfully, when considering important points such as electrode and titration mode selection. Furthermore, the translation of the titration method provides an opportunity to consider method optimization regarding titrant consumption and thus waste production.

Looking at the below three examples, the following changes are necessary for a method conversion from manual titration to semi-automated or automated titration.

For the potassium citrate assay:

  • Use of a combined pH electrode suitable for non-aqueous titration instead of the crystal violet indicator.
  • Increase glacial acetic acid solvent volume to immerse electrode.
  • Reduce sample size from 200 mg to 100 mg.
  • Use of the dynamic titration mode.

For the calcium hydroxide assay

  • Use of a combined Ca ion-selective electrode instead of the hydroxy naphthol blue indicator.
  • Reduce sample size from 1.5 g to 0.375 g.
  • Use of the dynamic titration mode.

For the limit of chlorine test of potassium bromide

  • Use of a combined silver electrode instead of the ferric ammonium sulfate indicator.
  • Increase water volume to immerse electrode.
  • Use of the dynamic titration mode.

These changes make a validation of the semi-automated or automated titration necessary. USP General Chapter <1225> Validation of Compendial Procedures provides an outline for which parameters need to be tested during a method validation.

Dynamic titration

In a dynamic titration, as the name implies, the titrant is added dynamically depending on the slope of the titration curve. For example, if the signal changes only slightly over several additions, the volume of the next increments will be increased and vice versa. Dynamic titration is similar to manual titration as the analyst will speed up or slow down the titrant addition speed as the color change begins to appear.

The advantage of this method is a high data density around the equivalence point leading to high resolution, better reproducibility, and a faster titration.

This paper summarizes the steps involved in converting an existing manual titration procedure to semi-automated or automated titration procedures. It discusses topics such as selecting the right electrode and titration mode.

Read also: Errors or Incidences During Analytical Method validation


  1. USP. Potassium Citrate. In: USP 42–NF 37. Rockville, MD: USP; 2020:3613.
  2. USP. Calcium Hydroxide. In: USP 42–NF 37. Rockville, MD: USP; 2020:701.
  3. USP. Potassium Bromide. In: USP 42–NF 37. Rockville, MD: USP; 2020:3600.
  4. USP. <301> Acid-neutralizing Capacity. In: USP–NF. Rockville, MD: USP; May 1, 2019.
  5. USP. <1225> Validation of Compendial Procedures. In: USP–NF. Rockville, MD: USP;
    May 1, 2019.

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