Non-aqueous titrimetric analysis

a titration of weakly acidic or basic substances that is carried out

using non-aqueous solvents
Complex organic medicinal agents
• Problems increased in quality control with the introduction of complex organic
medicinal (COM) agents
• Characteristics of COM agents:
• Poorly soluble
• Weakly reactive in water
• Typical quantitative procedures possessed drawbacks

Solution
Use of nonaqueous solvents
Use of nonaqueous solvents1
• Made possible a variety of direct titrimetric procedures
• Selective titration of an acidic or basic component
• Precautions:
1) moisture content should be kept at a minimum2
(less than 0.05%)
2) temperature should be controlled3
 Types of nonaqueous solvents
(based on the ability to donate or accept proton)

Aprotic Protophilic

Protogenic Amphiprotic
 ACID-BASE TITRATION
(NEUTRALIZATION)

AQUEOUS SOLUTION NON-AQUEOUS SOLUTION

BRONSTED-LOWRY LEWIS
definition of acids & bases definition of acids & bases
reaction between proton donors reaction between electron
& proton acceptors acceptors & electron donors
Factors to consider in choosing the solvent
• Solubility of the analyte
• Relative strength of the solvent1
• Sharpness of end point change
• Nonreactivity of the solvent with the analyte and titrant
Non-aqueous Titrimetry
• Used when the analyte
- is poorly soluble in water1, and
- hydrolyzes in the presence of water or reacts with water

• Advantages
- Elimination of poor solubility of substances
- Enhancement of weak reactivity of substances
- Selective titration by using suitable solvents
End Point in Nonaqueous Titrimetry
• indicators (either a weak acid or a weak base):
• react with H+ and produce the expected color changes, or
• give up their H+ and change color

• Equivalence Point
- ascertained potentiometrically, and
- an indicator is chosen which will give the sharpest color change for the least
increment of volume of titrant added near the equivalence point
Non-aqueous
acidimetric analysis
Titration Of Weak Bases
Analyte Titrant

Amines
Amine salts Perchloric acid in glacial acetic acid
Heterocyclic nitrogen compounds Dioxane
Alkali salts of organic acids Hydrogen bromide
Alkali salts of inorganic acids Organic sulfonic acids
Amino acids

Solvents1
Neutral2 Acetonitrile, Alcohols, CHCl3, benzene dioxane, ethyl acetate
Acidic3 formic acid, glacial acetic acid & propionic acid, acetic anhydride,
sulfonyl chloride
 Indicators

Crystal violet Methylrosanline Cl

Naphtholbenzein Malachite Green

Quinaldine red Methyl Orange

Methyl red Thymol blue

Standardization of perchloric acid
Titration Direct titration
Analyte Potassium biphthalate1
Indicator Crystal violet2
Titrant 1.0 N Perchloric acid
End point Emerald green
Notes Perform blank titration3
1. Occurs as a 70-72% mixture with water1,2
2. HClO4 undergoes spontaneous explosive decomposition
3. A powerful oxidizing agent and a strong acid

Precautions in the standardization of perchloric acid

Non-aqueous
Alkalimetric analysis
Titration of Weak Acids
Analyte titrant

Acid halides
Imides Amino acids Sodium methoxide solution1
Anhydrides Organic salts of Lithium methoxide solution
Phenols inorganic acids Sodium aminomethoxide2
Acids Enols Triphenylmethane3
sulfonamides

Solvents4
Ethylenediamine5, n-butylamine, morpholine, Dimethylformamide6 and pyridine
Sulfonamides
 TITRATION OF WEAK ACIDS
AZO VIOLET
ALKALIMETRY

THYMOL BLUE

O-NITROANILINE

THYMOLPHTHALEIN

P-HYDROXYAZOBENZENE
Volumetric Analysis:
Neutralization Reactions
End

Judah Israel O. Lescano, RPh

Department of Pharmacy
University of San Carlos