Handbook of Solvents - George Wypych - ChemTech - Ventech!

15.2.3 An innovative GC method 1113
15.2.3 DESCRIPTION OF AN INNOVATIVE GC METHOD TO ASSESS THE
INFLUENCE OF CRYSTAL TEXTURE AND DRYING CONDITIONS ON
RESIDUAL SOLVENT CONTENT IN PHARMACEUTICAL PRODUCTS
Christine Barthélémy
Laboratoire de Pharmacie Galénique et Biopharmacie
Faculté des Sciences Pharmaceutiques et Biologiques
Université de Lille II, Lille, France
Michel Bauer
International Analytical Sciences Department
Sanofi-Synthélabo Recherche, Toulouse, France
The presence of residual solvents (RS) in pharmaceutical substances occurs for various reasons.
Solvents are involved in all steps of raw material synthesis and pharmaceutical productions.
The search for the presence of RS in a pharmaceutical product and their
concentrations are now mandatory in any new monographs (as detailed in Chapter 16.2).
The RS remaining in the crystals of pharmaceutical products may be the cause of
health disorders because, when a drug is taken every day, chronic toxicity may occur.
The presence of RS may have other consequences, such as modifying stability,
organoleptic characters, pharmacotechnical parameters (flow properties, crystalline form,
compression ability) and biopharmaceutical characteristics, that may fluctuate according to
RS content (as detailed in chapters 14.21.1 and 16.2). It is therefore necessary to reduce the
residual solvents contained in crystalline particles as much as possible.
It is well known that solvents can exist in three different states within the crystals:
• Solvents adsorbed on the crystal faces: these are generally easily desorbed during
conventional drying because the binding forces between solvents and crystals are
very weak.
• Occluded solvents such as microdroplets in the crystal: these are often difficult to
extract. Generally, they can escape when the crystal is being dissociated:
- during grinding, potentially leading to clodding,
- during storage leading to very compact aggregates.
• Solvents bound to drug molecules in the crystal and known as “solvates”. These
bound solvents escape at a characteristic temperature, producing desolvated forms;
the solvate and the desolvated forms are two different crystalline entities that can
exhibit very different mechanical behaviors.
The main objective of any chemist crystallizing pharmaceutical raw materials should
be either the total elimination of the organic solvents or the significant reduction of RS level
in order to be below the regulatory limits. 1
15.2.3.1 Description of the RS determination method
There are several analytical methods to assess the RS content of drugs. Among them, the
gas chromatography (GC) is largely preferred. We refer to the chapter 16.2 for more details.
In direct injection methods, the products in which RS are included are usually dissolved in
an appropriate solvent and then directly injected into a gas chromatograph (GC). The main
problem with these techniques is that non-volatile substances are gradually retained in the
column, causing a rapid decrease in its sensitivity and efficiency; this is one of the reasons
why headspace techniques are increasingly used instead.