Handbook of Solvents - George Wypych - ChemTech - Ventech!

14.21.1 Use of solvents in manufacture of drugs 983
Table 14.21.1.3 Stabilizers used in selected solvents
Solvents Stabilizers
Dichloromethane Ethanol, 2-methyl-but-2-ene
Chloroform Ethanol (1% V/V) for avoiding the phosgene formation, 2-methyl-but-2-ene
Diethylether 2,6-di-tert-butyl-4 methylphenol (BHT)
Tetrahydrofuran BHT, p-cresol, hydroquinone, calcium hydride
14.21.1.2.1.6.4 Denaturing agents
This process is relevant primarily to ethanol. Common denaturing agents are: methanol,
isopropanol, ethyl acetate, toluene.
14.21.1.2.1.6.5 Transformation of the solvent during the chemical reaction
Solvents are rarely chemically inert. During the reactions where solvents are involved, they
can undergo chemical transformation generating impurities which can be found, for example
in the DS.
This is a huge field which cannot be exhaustively covered. We give below a few examples
of well-known side reactions.
• Acetone in acidic media is easily transformed into mesityl oxide:
So do not forget to test for it when performing residual solvents analysis on drugs.
• In basic medium the diketone-alcohol is obtained:
• DMF can be hydrolyzed in presence of hydrochloric acid:
• Acids undergoing reaction in alcoholic media can be partially transformed into
esters
• Transesterification reaction. Take care when, for example, recrystallization has to
be performed for a molecule containing an ester group:
• Aldehydes (even ketones) can be transformed in alcoholic solutions into ketals: