**2. Titrimetric techniques and their applications in pharmaceutical analysis**

Although about 200 years have elapsed since the publication of the first papers dealing with titrimetric analysis [31], the technique is still as widely used as ever in pharmaceutical analysis because of its robustness, cheapness, and capability for high precision, with also many advantages associated with these methods which include saving time and labor, and no need of using reference standards. In fact, titrimetric methods to these days are still widely used in pharmaceutical analysis simultaneously with the development of physicochemical methods for different measurements, as well as the spreading of non-aqueous titration method and potentiometric end point detection, expanding and improving the field of application of titrimetric methods, especially in the pharmaceutical analysis.

Titrimetry is the volumetric procedure for the determination of the concentration of the drug sample by adding a known concentration of the standard drug substance. This reacts quantitatively with the sample solution. Then a chemical reagent is used to detect the endpoint by the color change, the precipitate, or complex formation at the equivalent point of the titration. This reagent is known as the indicator.

#### **2.1 Types of titrations commonly used in the pharmaceutical analysis**

• Acid-base reactions: These reactions are based upon the titrations of the acidic or basic compounds by the consequent acids or bases. In addition, many drugs can be classified as acids or bases based on the presence of some functional group in the drug and these drugs can be analyzed using this type of reaction. In this type of reaction, H<sup>+</sup> reacts with OH ̶ to form H2O as in the following examples: These reactions are mainly based upon the reactions of the hydrogen ion and hydroxide ion to form water.

$$\rm H^{+} + \rm OH^{-} \rightarrow \rm H\_{2}O \tag{1}$$

A classic application of this type of titration is the determination of aspirin (acetylsalicylic acid) [32].

• Complexometric reactions: These types of titrations are based on the complexation reactions by using the complexing agent such as ethylenediaminetetraacetic acid (EDTA). these reactions are carried out by complex formation by combining ions by using complexing agents like EDTA. The endpoint is detected by using metal ion detectors.

• Precipitation reactions: These titrations are based on the precipitate formation.

Example: AgCl titrations: these reactions are carried out by the formation of the precipitate by combining the ions by using the precipitating reagents.

A precipitation reaction is a titration in which the reaction between the analyte and the titrants forms an insoluble precipitate. Most precipitation titrations involve standard Ag<sup>+</sup> as a titrant and Cl�, SCN� as an analyte. An example is a titration of chloride ions with silver nitrate solution to form a silver chloride precipitate. This type of reaction is used in pharmaceutical assays of many drugs, especially the drugs that are found as chloride salts such as bupropion hydrochloride (antidepressant drug) [33].

• Redox reactions: Redox reactions are more widely used in titrimetric pharmaceutical analysis than other types of reactions. The ions may exist in different oxidation states resulting in the possibility of a very large number of redox reactions. Many of these reactions satisfy the requirements for use in titrimetric analysis and applications are numerous. These reactions also are important for some basic functions of life, such as photosynthesis [34].

A good example of a redox reaction is the thermite reaction, in which iron atoms in ferric oxide lose (or give up) O atoms to Al atoms, producing Al2O3 [3].

$$\text{Fe}\_2\text{O}\_{3(s)} + 2\text{Al}\_{(s)} \to \text{Al}\_2\text{O}\_{3(s)} + 2\text{Fe}\_{(l)}\tag{2}$$

The successful application of a redox reaction to titrimetric analysis requires, among other things, the means for detecting the equivalence point. Therefore, it is worth examining the changes that occur in variations that are most pronounced in the region of the equivalence point.

In the pharmaceutical formulation, a common application of this type of titration involves iodine I2, potassium permanganate KMnO4, and cerium (VI). The direct titration method against iodine (sometimes termed iodimetry) refers to titrations with a standard solution of iodine.

(I2 + 2e� ! 2I� iodine is oxidizing agent)

Iodine has low solubility in water but the complex I3 �, is very soluble. So, in the most direct titrations with iodine (iodimetry) iodine solutions are prepared by dissolving I2 in a concentrated solution of KI (potassium iodide). This type of titration (iodimetry) can be used in the assay of many pharmaceutical compounds such as ascorbic acid (vitamin C), benzylpenicillin, ampicillin, cloxacillin, methicillin, carbenicillin, cefazolin, cephalothin, cephaloglycin, cephalexin, cephalosporin C, 7-aminocephalosporanic acid, and cefoxitin [35, 36].

• The titrant is (I2 + KI) solution.

(that can be standardized against Na2S2O6; sodium thiosulfate).


*Spectrophotometric/Titrimetric Drug Analysis DOI: http://dx.doi.org/10.5772/intechopen.109364*

While the indirect titration method (sometimes termed iodometry) deals with the titration of iodine liberated in chemical reactions.

(2I� ! I2 + 2e� iodine is reducing agent)

The second method (Iodometry) called indirect or back titration that involves an excess of KI being added, reducing the analyte and liberating I2. The amount of I2 produced is then determined by a back titration using Na2S2O3 as a reducing titrant. The iodometry titration can be used in the assay of many pharmaceutical compounds such as amoxicillin and diethylcarbamazine citrate [14, 37–39].

The titrant is a thiosulfate solution,


Potassium permanganate (KMnO4) and cerium (IV) also are widely used as an oxidizing titrant in the assay of pharmaceutical compounds such as famotidine citrate, diethylcarbamazine citrate, minoxidil, hydrogen peroxide and Pantoprazole [40–44], Vitamin C, Ofloxacin, and ketotifen [45–47], respectively.

• Non-aqueous reactions: These reactions are based upon the titrations by using the non-aqueous titrants. Non-aqueous titrations are titrations carried out in the absence of water. In potentiometric titrations, absolute potentials or potentials concerning standard half-cells are not usually required, and measurements are made while the titration is in progress. The equivalence point of the reaction will be revealed by a sudden change in the potential in the plot of e.m.f. reading against the volume of the titration solution, and we can determine the end-point graphically. The graphical method (the differential method) involves a plot of the change in potential per unit change in the volume of reagent (ΔE/ΔV) as a function of the average volume of the reagent added. The end-point is taken as the maximum in the curve and is obtained by extrapolation of the experimental points (**Figure 1**).

**Figure 1.** *Potentiometric titration curve.*

Non-aqueous titration is the most common titrimetric procedure used in the pharmaceutical assays of many drugs [7, 15, 27]. Non-aqueous titrations are widely used in Volumes I and II of the British Pharmacopeia for the assay of drug substances. A large number of drugs are either weakly acidic or weak base. The weak acids are usually titrated with tetrabutylammonium hydroxide (Bu4NOH) or potassium methoxide (CH3OK) in dimethyl formamide (DMF) as a solvent. Weak bases are dissolved in glacial acetic acid and titrated with perchloric acid (HClO4). For weak bases, the titration medium usually used for non-aqueous titration of bases is perchloric acid in acetic acid. However, perchloric acid is not a primary standard substance, so it can be standardized using potassium hydrogen phthalate (KHC8H4O4) in a glacial acetic acid, and acetous crystal violet as an indicator.

The overall reactions with drug base occurring as follows:

$$\text{HClO}\_4 + \text{basic drug} \to \text{basic drug H}^+ + \text{ClO}\_4^- \tag{3}$$

That is, the perchloric acid acts as a monoprotic acid and 1 mole of perchloric acid is equivalent to 1 mole of the basic drug. British Pharmacopeia (BP) recommends a non-aqueous titration as a reference method for the assay of methyldopa which is a cardiovascular drug using 0.1 M perchloric acid as titrant and crystal violet solution as indicator. In general, the reaction taking place between a primary amine and perchloric acid may be expressed as follows:

$$\text{RNH}\_2 + \text{HClO}\_4 \rightarrow [\text{RNH}\_3]^+ + \text{ClO}\_4^- \tag{4}$$

Also, several drugs are weakly acidic. Such substances can be titrated against strong bases like potassium methoxide and sodium methoxide, in solvents like toluene-methanol. The principle is similar to the titration of weak bases against perchloric acid. Potassium methoxide and sodium methoxide are not primary standard substances. So, they can be standardized by dimethylformamide (DMF, H � CON CH ð Þ<sup>3</sup> <sup>2</sup>) and benzoic acid using methanolic thymol blue as an indicator. Ethosuximide, for example, is an antiepileptic drug and can be assayed by nonaqueous titration. The drug can be prepared in DMF. The titration can be done with sodium methoxide using azo-violet as an indicator.
