Diazotization Titrations in Pharmaceutical Analysis

As introduced in 1853 for the application in the synthetic dye industries, this Diazotization Titrations in Pharmaceutical Analysis is the conversion of any primary aromatic amine into a diazonium compound. Moreover, the aromatic amines are the group of organic compounds with an aromatic ring on their amine. On the other hand, the diazonium compounds are the group of organic compounds having a functional group R-N+2X. R can be an alkyl or aryl group, and X is the inorganic part.

Peter Griessin was the first person who proposed the mechanism reaction for the diazotization titration. According to the reactions, the given primary aromatic group shall react with the sodium nitrite to form a diazonium compound or diazonium salt. Moreover, the medium of this reaction is acidic. Let’s study the principle of diazotization and types of diazotization titrations.

Principle of Diazotization Titrations

The principle of diazotization titration in the pharmaceutical analysis is that the given sample of primary aromatic amine will react with sodium nitrite to yield a diazonium salt in the presence of an acid (For example, HCl).  The chemical reaction of this process is as follows:

R-NH2+ NaNO2+ HCl→ R-N+≡ N-Cl–+ NaCl + H2O

Diazotization Titrations

For the direct diazotization method, we shall use NaNO2 (in an acidic medium, as mentioned earlier). NaNO2 will give out HNO2, and we can analyse the number of primary amine groups with free –NH2 groups easily by measuring the volume of NaNO2 in the solution. The chemical reaction of this process is as follows:

NaNO2 + HCl →HONO + NaCl 

ArNH2 + HONO + HCl →ArN2Cl + 2H2O 

We can detect the excess portion of NaNO2 left in the solution by starch paper test or an indicator. The excess NaNO2 indicates that the reaction has reached its endpoint. The I2 released at the end will react with the starch to give a blue colour. It is important to note that it will only happen in the presence of an inorganic acid. Thus, the chemical reaction for the test of it with the starch iodide paper or solution is as follows:

KI + HCl →HI+ KCl

 2HI +2HONO→ I2 +2NO +2H2O (excess) 

I2 + Solution of paste of starch→ blue colour (endpoint) 

Types of Diazotization Titrations

Based on the diazotization titration, it can be of three primary methods:

• Direct Method: This method involves treating the given amino group with an acid solution to yield the diazonium salts of diazonium compounds. This solution will be kept in the ice water to maintain the temperature between 0-5 °C. Now, titrate it with sodium nitrate and wait for the endpoint. 
• Indirect Method: The application of the indirect method of titration is for insoluble diazonium salts. In this method, we shall have to add the excess nitrous acid to the titration solution sample. As it is an insoluble diazonium salt, we have to titrate i9t against some other titrant. 
• Other Methods: The other method involves the conversion into diazo oxides rather than the diazo compounds, as they tend to be more stable. 

Factors Affecting Diazotization Titrations

Some of the factors that will affect the diazotization titration are as follows:

• pH of NaNO2
• the concentration of the acid that we will use for the titration
• the temperature of the reaction
• Time duration of the reaction
• Efficiency (fast or slow) of attached diazotized groups.

Conditions required for Diazotization Titrations

Some of the basic conditions that are necessary to maintain for the diazotization titration to proceed are as follows:

• Maintaining the Temperature of the Reaction: All reactions require their appropriate temperature to take place. Increasing or decreasing this optimum temperature can greatly affect the reaction rate and stop the reaction. Similarly, the diazonium compounds formed after the reactions easily decompose at higher temperatures. Therefore, it is necessary to maintain the optimum temperature (i.e. between 0 to 5°C) to get the best result without errors. Moreover, at optimum temperature, more stable diazo compounds are formed. 
• Rate of Titration: The rate of reaction varies with different compounds. Similarly, the rate of reaction of amino compounds with HONO will differ. We can classify them as fast diazotisable or slow diazotized based on their conversion rate. 

Compounds containing nitrous oxide groups, carboxylic groups, sulpha groups etc. come under the category of slow diazotisable compounds. Examples: sulphanilic acid, anthranilic acid etc. 

Compounds with only amino groups or sometimes –CH3 or hydroxyl groups come under fast diazotisable compounds. Examples: aminophenol and aniline.

Application of Diazotization Titrations in Pharmaceutical Analysis

The main application of diazotization titrations in pharmaceuticals is the analysis of sulphonamides.

Conclusion

The diazotization titration in the pharmaceutical analysis involves the conversion of the given primary aromatic amines into the specific diazonium compounds. Peter Griessin was the first person who proposed the mechanism reaction for the diazotization titration. The given primary aromatic group will react with the sodium nitrite to yield a diazonium salt in an acidic medium. Some of the factors that will affect the diazotization titration are the pH of NaNO2, the concentration of the acid used in the titration, the temperature of the reaction and the Time duration of the reaction. The types of diazotization titration can be classified into three categories: direct method, indirect method and other methods.