Handbook of Solvents - George Wypych - ChemTech - Ventech!

14.21.1 Use of solvents in manufacture of drugs 985
We have listed in Table 14.21.1.4. the most commonly used solvents.
Table 14.21.1.4 Solvents used in formulation
Water
Ethyl acetate
Ethyl alcohol (denaturated with butanol and isopropanol)
Isopropyl alcohol (denaturated with methyl ethyl ketone)
Methanol
Acetone
Dichloromethane
Chloroform
Hexane
Cyclohexane
Polyethylene glycol (low molecular weight)
Manufacturers try progressively to replace the formulations using organic solvents
such as chloroform, dichloromethane, cyclohexane belonging to the class 2 (ICH classification
see Chapter 16.2), for example by developing aqueous coatings.
14.21.1.2.2.3 What should be the quality?
Taking into account the fact that the solvents used in the DP manufacturing process, either
as a component of the formulation or as a residual solvent, will be absorbed by the patient,
their quality must be of the highest standard. From a regulatory point of view, in almost every
country if not all, it is mandatory to use solvents covered by a pharmacopoeial monograph
(e.g., European Pharmacopoeia, USP, JP, local Pharmacopoeias). Some examples are
given below.
14.21.1.3 Impacts of the nature of solvents and their quality on the
physicochemical characteristics of raw materials and DP.
14.21.1.3.1 Raw materials (intermediates, DS, excipients)
The impurities contained in the solvents could have several effects on the raw materials:
• When the solvents are removed, non-volatile or less volatile impurities will be
concentrated in raw materials.
• They can induce chemical reactions leading to side products.
• They can affect the stability of the raw material considered.
• They can modify substantially the crystallization process.
14.21.1.3.1.1 Concentration of less volatile impurities
Due to the potential concentration of these impurities, they should be tested for in both DS
and excipients and even in intermediates of synthesis if the latter constitute the penultimate
step of the synthesis and if solvents belong to class 1 or class 2 solvent (see Chapter 16.2).
14.21.1.3.1.2 Side reactions
This case has already been illustrated (see paragraph 14.21.1.2.1.6.5). The skills of the
chemist together with those of the analyst are needed to ensure that the presence of unexpected
impurities can be detected. By way of example, the reactions involving the keto-enol
tautomerism deserve to be mentioned. The equilibrium is very sensitive to the solvent so
that the presence of other solvents as impurities in the main solvent can modify the
keto-enol ratio leading to irreproducibility in the chemical process. 13,14
14.21.1.3.1.3 Consequences for stability
Some solvents, as mentioned in the paragraph 14.21.1.2.1.5, can contain very active entities
such as aldehydes and peroxides. For example, if the raw material contains primary or sec-