Handbook of Solvents - George Wypych - ChemTech - Ventech!

978 Michel Bauer, Christine Barthélémy
One or several active compounds (DS) are prepared by organic synthesis, extracted
from vegetable, animals, micro-organisms or obtained by biotechnology. The DS is generally
associated in the product with several excipients of chemical, mineral or biological in
nature either as monomers or as polymers.
The goal is to formulate a processable DP stable over the time and allowing the active
substance to be released in vitro and in vivo. Obviously the formulation is designed in relation
to the route of administration:
• oral route solid dosage forms (e.g., tablets, capsules, etc.) drinkable solutions etc.
• ORL route (nasal solutions, spray)
• local route (suppositories, transdermal systems, eye-drop formulation, spray)
• intravenous and intramuscular route (injectable solution, lyophilizate, etc.)
At practically every step of the manufacture of the drug substance and the excipients,
solvents including water are utilized. This is equally true for the preparation of the pharmaceutical
formulations.
Ideally we would like to have available a universal stable solvent, ultrapure, non-toxic
and which does not affect the solutes. This is an old dream of the alchemists who searched
for a long time for the “Alkahest” or “Menstruum universal” as it was named by
Paracelsus. 1
The fact that a solvent is not a totally inert species allows it to play an important role in
chemical equilibria, rates of chemical reactions, appearance of new crystalline forms, etc.
and consequently contributes to the great wealth of compounds which the chemists are able
to produce.
But of course, there are drawbacks in using solvents. Because there are not totally inert
they may favor the formation of undesirable impurities in the intermediates of synthesis and
in the DS. Regarding the manufacture of the DP, the solvents, including water, may induce
either polymorphic transformations or formation of solvates (hydrates) which, after drying,
could lead to a desolvated solvate with quite different physical properties impacting potentially
either positively or negatively on the DP performance. 2
Another crucial aspect which deserves to be discussed, is the notion of purity. Impurities
present in solvents could have an impact on the stability of drugs, for example, or on
the crystallization process.
Last, but not least, the toxicological aspects should be taken into account. Numerous
solvents show different kinds of toxicity and this should be a matter of concern in relation to
the health of workers exposed to them. 3 But ultimately residual solvents still present in the
DS and DP have to be assessed and systematically limited.
We are now going to consider several aspects of the use of solvents in the manufacture
of drug substances (DS) and drug products (DP) including their quality (purity) and influence
on the quality, stability and physico-chemical characteristics of pharmaceutical products.
The issue of residual solvents in pharmaceutical products will be considered in
Chapter 16.2 and will focus amongst other things on the corresponding ICH Guideline. 4